Total synthesis of redox-active 1.4-naphthoquinones and their metabolites and their therapeutic use as antimalarial and schistomicidal agents

ABSTRACT

Naphthoquinones, azanaphthoquinones and benxanthones, their process of synthesis and methods of their use as antimalarial or antischistosomal agents.

The present invention relates to a new process for synthesizing1.4-naphthoquinones and their metabolites and to their application intherapeutics.

Plasmodium falciparum and Schistosoma mansoni are blood feedingparasites digesting the host's hemoglobin. and detoxifying the toxicheme into an insoluble polymer called hemozoin.

Plasmodium parasites are exposed to elevated fluxes of reactive oxygenspecies during the life cycle in the human host and therefore highactivities of intracellular antioxidant systems are needed. The mostimportant antioxidative system consists of thiols which are regeneratedby disulfide reductases; these include three validated drug targets theglutathione reductases (GR) of the malarial parasite Plasmodiumfalciparum and of human erythrocytes as well as the thioredoxinreductase of P. falciparum (Schirmer et al. Angew. Chem. Int. Ed. Engl.1995, 34. 141-54; Krauth-Siegel et al. Angew. Chem. Int. Ed. Engl. 2005,44, 690-715). One validated target against the malarial parasitePlasmodium falciparum is the enzyme glutathione reductase which reducesglutathione disulfide to its thiol form glutathione on the expense ofNADPH. Glutathione is implicated in the development of chloroquineresistance: an elevation of the glutathione content in P. falciparumleads to increased resistance to chloroquine, while glutathionedepletion in resistant strains restores sensitivity to chloroquine(Meierjohan et al. Biochem. J. 200, 368, 761-768). High intracellularglutathione levels depend inter alia on the efficient reduction ofglutathione disulfide by GR and by reduced thioredoxin (Kanzok et al.Science 2001, 291, 643-646). The contribution to the reversal of drugresistance or to a synergistic effect by GR inhibitors like methyleneblue is currently investigated for the commonly used antimalarial drugschloroquine, amodiaquine, artesunate in clinical trials (Zoungrana etal. PLoS One, 2008. 3:e1630; Meissner et al. Malar J. 2006. 5:84;Akoachere et al. Antimicrob. Agents Chemother. 2005, 49, 4592-7).Derivatives of menadione per se were shown to be potent inhibitors bothof human and Plasmodium falciparum glutathione reductases acting in thelow micromolar range in parasitic assays with P. falciparum in cultures(Biot et al. J. Med. Chem. 47. 5972-5983; Bauer et al. J. Am. Chem. Soc.2006. 128. 10784-10794). The dual drugs combining a 4-aminoquinoline anda menadione-based GR inhibitor exhibited high antimalarial potencies inthe low nanomolar range in the malarial assays in vitro.(Davioud-Charvet et al. J. Med. Chem. 2001, 44, 4268-4276; Friebolin etal., J. Med. Chem. 2008. 51. 1260-77; Wenzel et al. J. Med. Chem. 2010.53, 3214-26).

The malarial parasite Plasmodium falciparum digests a large amount ofits host cell hemoglobin during its erythrocytic cycle as source ofessential nutrients (Zarchin et al. Biochem. Pharmacol. 198, 35,2435-2442). The digestion is a complex process that involves severalproteases and takes place in the food vacuole of the parasite leading tothe formation of iron II ferroprotoporphyrin (FPIX) (Goldberg et al.Parasitol. Today. 1992, 8, 280-283) as toxic byproduct for the parasitewhich is immediately oxidized to FPIX(Fe³⁺). Due to the toxicity of FPIXthe parasites have developed a detoxification process in whichFPIX(Fe³⁺) (hematin) is polymerized forming inert crystals of hemozoinor malaria pigment (Dorn et al. Nature 1995, 374, 269-271). FPIX(Fe²⁺)is an inhibitor of hematin polymerization (Monti et al. Biochemistry1999. 38, 8858-8863). Early observations indicated that free FPIX(Fe³⁺)is able to form complexes with aromatic compounds bearing nitrogen, e.g.pyridines, 4-aminoquinolines (Cohen et al. Nature 1964, 202, 805-806;Egan et al. J. Inorg. Biochem. 2006, 100, 916-926) and it is now wellestablished that 4-aminoquinolines can form μ-oxodimers with FPIX thuspreventing the formation of hemozoin. Consequently, an increase of freeheme concentration in the food vacuole is responsible for killing theparasite (Vippagunta et al. Biomed. Biochim. Acta 2000, 1475, 133-140).In the presence of reactive oxygen species iron-porphyrin complexes(e.g. free heme) are catalysts for oxidation reactions. Released inlarge quantities in the food vacuole of the parasite they are thought tostrongly influence the activity of a drug under the specific acidicconditions of the malarial food vacuole. Drug metabolites can be moreactive than its precursor (pro-drug effect) or toxic (Bernadou et al.Adv. Synth. Catal. 2004, 346, 171-184).

The reduction of methemoglobin(Fe³⁺) into hemoglobin(Fe²⁺) is of greatimportance in the treatment of malaria. Since the malarial parasite ismuch more capable of using methemoglobin as nutrient and digestsmethemoblobin faster than hemoglobin the reduction of methemoglobin canbe used to slow down the parasite's methemoglobin digestion by reducingits concentration. A second reason to target the reduction ofmethemoglobin is that methemoglobin, the ferric form of hemoglobin, isnot capable of oxygen transport. High levels of methemoglobin are foundduring Plasmodium vivax infections (Anstey et al. Trans. R. Soc. Trop.Med. Hyg. 1996, 90, 147-151). A reduced oxygen carrying capacity ofblood due to anaemia is even worsened by reduction in oxygen carryingcapacity from even a modest concentration of methemoglobin leading to animpaired supply of oxygen for the tissue; a specific situation observedin cerebral malaria.

The two major antioxidant defense lines in Plasmodium are provided bythe glutathione and the thioredoxin systems. Both systems areNADPH-dependent and are driven by homodimeric FAD-dependentoxido-reductases, namely glutathione reductase (PfGR) and thioredoxinreductase (PfTrxR). Both GRs from the human erythrocyte and from themalarial parasite are essential proteins for the survival of themalarial parasite infecting red blood cells and were identified astargets of antimalarial drugs. They maintain the redox equilibrium inthe cytosol by catalyzing the physiological reaction:NADPH+H⁺+GSSG→NADP⁺+2 GSH, in particular in the course of thepro-oxidant process of hemoglobin digestion in the intraerythrocyticplasmodial cycle. The parasite evades the toxicity of the released hemeby expressing two major detoxification pathways, i.e. hemozoin formationin the food vacuole and an efficient thiol network in the cytosol.Hemozoin formation is inhibited by 4-aminoquinolines such as chloroquine(CQ) and heme FPIX(Fe²⁺). The thiol network maintained by GR isinhibited by numerous redox-cyclers including 1,4-naphthoquinonesdisclosed in patent application WO in the name of the inventors,phenothiazinium derivatives as methylene blue (MB) and the naturalphenazine pyocyanin (PYO), and nitroaromatics. Methylene blue, anefficient GR subversive substrate, was the first synthetic antimalarialdrug used in human medicine at the beginning of the 20^(th) century butwas abandoned with the launch of chloroquine in the 40s′. Its reducedform (LMB) is known to reduce Fe³⁺ to Fe²⁺ from both methemoglobin(MetHb) and heme (FPIX) species.

Since the malarial parasite Plasmodium falciparum multiplies in humanerythrocytes, most drugs are directed against this stage of the lifecycle of the parasite.

The most administered drugs are chloroquine and 4-aminoquinolinederivatives, and artemisinin and arthemether derivatives. Presentmalaria treatment (recommended by WHO) is based on combination therapy:artemisinin combined therapy (ACT). Highly and multi-drug-resistantPlasmodium strains spread all over the world. For instance, very recentstudies showed that resistant Plasmodium falciparum strains toartemether (artemisinin analogue) appeared in French Guiana and Senegal(Jambou et al. Lancet. 2005, 366, 1960-3; XX). Also, decreased in vitrosusceptibility of Plasmodium falciparum isolates to artesunate,mefloquine, chloroquine, and quinine in Cambodia from 2001 to 2007 wereobserved (Noranate N et al. PLoS One 2007, 2:e139; Lim et al.Antimicrob. Agents Chemother. 2010, 54, 2135-42).

The chemotherapy of schistosomiasis is currently based on only one drug,Praziquantel (PZQ). Drug resistances developed by both parasites areemerging and there is an urgent need for new antiparasitic drugs. WhilePZQ is very effective in schistosomiasis treatment and has a very lowtoxicity, it has limited action against larval parasites. This leads toineffective cures in areas of high transmission. Furthermore, there isevidence of evolving PZQ-resistant parasites in Egypt, suggesting theurgency for the development of novel schistosomicidal agents. Clinicaldrug resistance against PZQ has also been noted in Kenya (Melman S D etal. PLoS Negl. Trop. Dis. 2009, 3:e504). Artemisinin-basedantischistosomal drugs have good activity against larval parasites, butlimited activity against adult parasites. The use of the same molecules(ex: artemisinin) to treat both malaria and schistosomiasis put theantimalarial application at risk if multi-resistant parasites appear.

There is therefore still a need for compounds having efficiency againstmalaria and schistosomiasis without the usual drawbacks of the existingdrugs. Furthermore, there is a need for compounds which are easy toformulate in pharmaceutical compositions.

In international application WO 2009/118327 the inventors disclosed anew series of compounds based on the 2-methyl-1,4-naphthoquinone core(named menadione). These compounds were 3-benzylmenadione derivatives(benzylNQ) and most of them were synthesized in one step withsatisfactory yields. The series was tested in in vitro tests against thechloroquine-sensitive strain 3D7, the chloroquine-resistant strain K1,the multidrug-resistant strain Dd2 and against a Pf-GHA parasite strainin vitro. The compounds showed antimalarial effects in the low nM rangewhile displaying moderate cytotoxicity in the μM range and no hemolysisof red blood cells at therapeutic doses. The most active compounds werealso tested in a mouse model infected by P. berghei displayingsignificant decrease in parasitemia at 30 mg/kg (ip and po),

Now the inventors developed new methodologies for total synthesis ofpolysubstituted 3-benzylmenadione derivatives and aza analogues. Theyalso studied the potential metabolism of these compounds, synthesizedthe putative metabolites and investigated the mechanism of action. Themetabolites, the benz[c]-xanthen-7-ones (benzxanthones), were tested inthe hematin polymerization assay.

The inventors also studied new uses of the molecules, described in thepresent patent application, as antiparasitic agents to targetblood-feeding parasites, including the protozoans Plasmodium, Eimeriaand Babesia, the helminths including the worm Schistosoma, and morebroadly the external blood-feeding parasites like fleas and ticks, totreat humans and animals (cattle, pets), in human and veterinarymedicines, as prophylactics or as treatments, respectively.

In the publication Journal of Medicinal Chemistry 1991, Vol. 34, N^(o) 1p. 270 a product code-named n^(o) 25 belonging to the chemical family ofthe Pyridylmethyl naphtoquinones is disclosed.

Consequently, a first object of the invention are compounds of formula(I)

wherein:

-   -   either X₁, X₂, X₃ and X₄ represent all carbon atoms,    -   either one of X₁, X₂, X₃ and X₄ represents a nitrogen atom and        the three others represent carbon atoms,    -   either X₁ and X₄ represent a nitrogen atom and both X₂ and X₃        represent carbon atoms,    -   the bond - - - - - between O in position 17 and X₁₀ represents        no bond or a single bond,    -   the bond        represents either a single bond or a double bond,    -   X₅ represents CO or CH₂ or CHOH,    -   X₆, X₇, X₈, X₉ and X₁₀ represent all carbon atoms or one of them        represents a nitrogen atom and the four others are carbon atoms,

with the proviso that

i) when the bond - - - - - between O17 and X₁₀ represents a single bond,then the bonds

between atoms in positions C1/O18 and C4/O17 are single bonds, the bondsbetween carbons in positions C1/C2 and C3/C4 are double bonds, the bondbetween carbons in positions C2/C3 is a simple bond, and R represents ahydrogen atom or an acetyl group and X₁₀ is not a nitrogen atom and

ii) when the bond - - - - - between O17 and X₁₀ represents no bond, thenR does not exist and the bonds

between atoms C1/O18 and C4/O17 are double bonds, the bonds betweencarbons in positions C1/C2 and C3/C4 are simple bonds, the bond betweencarbons in positions C2/C3 is a double bond, and

X₁, X₂, X₃ and X₄ when they are carbon atoms being optionallysubstituted by:

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,    -   X₆, X₇, X₈, X₉, X₁₀—except when atoms O17 and X₁₀ are bound by a        simple bond and X₁₀ is a quarternary carbon atom—being        optionally substituted by:    -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,    -   a difluoromethoxy group,    -   a difluoromethyl group,    -   —COOH,    -   —COO(C₁-C₄)alkyl group,    -   —CONR₁(CH₂)_(m)CN, with R₁ being a hydrogen atom or a linear or        branched (C₁-C₄)alkyl group and m=1, 2 or 3,    -   —CSNR₁(CH₂)_(m)CN, with R₁ being a hydrogen atom or a linear or        branched (C₁-C₄)alkyl group m=1, 2 or 3,    -   —CONR₁Het with R₁ being a hydrogen atom or a linear or branched        (C₁-C₄)alkyl group, Het representing a pyridine-2-yl group, said        group optionally substituted by an amino group in -6 or by a        —CONH₂ group in -5,    -   —NO₂,    -   —CN,    -   —NR₂R₃ with R₂ and R₃ representing each independently a hydrogen        atom, an amino protecting group selected from the group        comprising Boc group and (C₁-C₄)alkyl group, or R₂ and R₃        forming with the nitrogen atom which bears them a cyclic group        selected from the group comprising morpholine, piperidine, and        piperazine groups, said cyclic groups being optionally        substituted,    -   an aryl group or an aryl group substituted by one or several        substituents selected from the group comprising a (C₁-C₄)alkyl        group, a —NO₂ group, a —COOR₄ with R₄ selected from a hydrogen        atom and a linear or branched (C₁-C₄)alkyl group, a —NR₅R₆ with        R₅ and R₆ independently selected from the group comprising a        hydrogen atom and a linear or branched (C₁-C₄)alkyl group,    -   a heterocyclic group selected from the group comprising        morpholinyl group or piperidinyl, or piperazinyl group, each of        said group being optionally substituted by one or several        substituents selected from the group comprising a linear or        branched (C₁-C₄)alkyl group, —COOCH₂CH₃, or a group

and the pharmaceutically acceptable derivatives thereof,

for their use as antiparasitic agents to target blood-feeding parasites,

with the proviso that when the blood-feeding parasite is Plasmodium,then when X₁, X₂, X₃ and X₄ are all carbon atoms, or when X₁ is anitrogen atom, and X₂, X₃ and X₄ are all carbon atoms, then at least oneof X₆, X₇, X₈, X₉ and X₁₀ represents a nitrogen atom.

The present invention also deals with compounds of formula (Ip)

wherein:

-   -   either X₁, X₂, X₃ and X₄ represent all carbon atoms,    -   either one of X₁, X₂, X₃ and X₄ represents a nitrogen atom and        the three others represent carbon atoms,    -   either X₁ and X₄ represent a nitrogen atom and both X₂ and X₃        represent carbon atoms,    -   the bond - - - - - between O in position 17 and X₁₀ represents        no bond or a single bond,    -   the bond        represents either a single bond or a double bond,    -   X₅ represents CO or CH₂ or CHOH,    -   X₆, X₇, X₈, X₉ and X₁₀ represent all carbon atoms or one of them        represents a nitrogen atom and the four others are carbon atoms,

with the proviso that

i) when the bond - - - - - between O17 and X₁₀ represents a single bond,then the bonds

between atoms in positions C1/O18 and C4/O17 are single bonds, the bondsbetween carbons in positions C1/C2 and C3/C4 are double bonds, the bondbetween carbons in positions C2/C3 is a simple bond, and R represents ahydrogen atom or an acetyl group and X₁₀ is not a nitrogen atom and

ii) when the bond - - - - - between O17 and X₁₀ represents no bond, thenR does not exist and the bonds

between atoms C1/O18 and C4/O17 are double bonds, the bonds betweencarbons in positions C1/C2 and C3/C4 are simple bonds, the bond betweencarbons in positions C2/C3 is a double bond, and

X₁, X₂, X₃ and X₄ when they are carbon atoms being optionallysubstituted by:

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

X₆, X₇, X₈, X₉, X₁₀—except when atoms O17 and X₁₀ are bound by a simplebond and X₁₀ is a quarternary carbon atom—being optionally substitutedby:

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,    -   a difluoromethoxy group,    -   a difluoromethyl group,    -   —COOH,    -   —COO(C₁-C₄)alkyl group,    -   —CONR₁(CH₂)_(m)CN, with R₁ being a hydrogen atom or a linear or        branched (C₁-C₄)alkyl group and m=1, 2 or 3,    -   —CSNR₁(CH₂)_(m)CN, with R₁ being a hydrogen atom or a linear or        branched (C₁-C₄)alkyl group m=1, 2 or 3,    -   —CONR₁Het with R₁ being a hydrogen atom or a linear or branched        (C₁-C₄)alkyl group, Het representing a pyridine-2-yl group, said        group optionally substituted by an amino group in -6 or by a        —CONH₂ group in -5,    -   —NO₂,    -   —CN,    -   —NR₂R₃ with R₂ and R₃ representing each independently a hydrogen        atom, an amino protecting group selected from the group        comprising Boc group and (C₁-C₄)alkyl group, or R₂ and R₃        forming with the nitrogen atom which bears them a cyclic group        selected from the group comprising morpholine, piperidine, and        piperazine groups, said cyclic groups being optionally        substituted,    -   an aryl group or an aryl group substituted by one or several        substituents selected from the group comprising a (C₁-C₄)alkyl        group, a —NO₂ group, a —COOR₄ with R₄ selected from a hydrogen        atom and a linear or branched (C₁-C₄)alkyl group, a —NR₅R₆ with        R₅ and R₆ independently selected from the group comprising a        hydrogen atom and a linear or branched (C₁-C₄)alkyl group,    -   a heterocyclic group selected from the group comprising        morpholinyl group or piperidinyl or piperazinyl group, each of        said group being optionally substituted by one or several        substituents selected from the group comprising a linear or        branched (C₁-C₄)alkyl group, —COOCH₂CH₃, or a group

and the pharmaceutically acceptable derivatives thereof,

for their use as antiparasitic agents to target blood-feeding parasites,

with the proviso that when the blood-feeding parasite is Plasmodium,then when X₁, X₂, X₃ and X₄ are all carbon atoms, or when X₁ is anitrogen atom, and X₂, X₃ and X₄ are all carbon atoms, then at least oneof X₆, X₇, X₈, X₉ and X₁₀ represents a nitrogen atom.

According to the instant invention, blood-feeding parasites includes theprotozoans Plasmodium, Eimeria, and Babesia, the helminths including theworm Schistosoma, and more broadly the external blood-feeding parasiteslike fleas and ticks. Thus the compounds according to the invention maybe used to treat humans and animals (cattle, pets), in human andveterinary medecines, as prophylaxics or as treatments, respectively.The following blood-feeding parasites may be cited Schistosoma mansoni,Schistosoma haematobium, Schistosoma japonicum, Schistosoma mekongi,Schistosoma intercalatum, Schistosoma bovis and Schistosoma nasale,Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodiummalariae, Babesia divergens, Babesia microti, and all Eimeria spp. beingprincipal cause of coccidiosis, highly pathogenic, especially in youngdomesticated mammals, herbivores, and birds.

According to the present invention, a “pharmaceutically acceptable salt”is a pharmaceutically acceptable, organic or inorganic acid or base saltof a compound of the invention, Representative pharmaceuticallyacceptable salts include, e.g., alkali metal salts, alkali earth salts,ammonium salts, water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, hydrochloride, edetate, edisylate,estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts. Apharmaceutically acceptable salt can have more than one charged atom inits structure. In this instance the pharmaceutically acceptable salt canhave multiple counterions. Thus, a pharmaceutically acceptable salt canhave one or more charged atoms and/or one or more counterions.

According to the invention, the term “halogen” refers to bromine atom,chlorine atom, fluorine atom or iodine atom.

According to the invention, the term “alkyl” refers to a straight orbranched chain, saturated hydrocarbon having the indicated number ofcarbon atoms. A (C₁-C₄) alkyl is meant to include but is not limited tomethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl. An alkylgroup can be unsubstituted or optionally substituted with one or moresubstituents selected from halogen atom, hydroxy group or amino group.

The term “alkoxy” refers to a —O-alkyl group having the indicated numberof carbon atoms. A (C₁-C₄)alkoxy group includes —O-methyl, —O-ethyl,—O-propyl, —O-isopropyl, —O-butyl, —O-sec-butyl, —O-tert-butyl.

The term “thioalkoxy” refers to an S—O-alkyl group having the indicatednumber of carbon atoms. A thio(C₁-C₄)alkoxy group includes S—O-methyl,S—O-ethyl, S—O-propyl, S—O-isopropyl, S—O-butyl, S—O-sec-butyl,S—O-tert-butyl.

The term “aryl” refers to a 6- to 18-membered monocyclic, bicyclic,tricyclic, or polycyclic aromatic hydrocarbon ring system. Examples ofan aryl group include phenyl, naphthyl, pyrenyl, anthracyl, quinolyl,and isoquinolyl.

The term “heteroaryl” refers to small sized heterocycles including di-and tri-azoles, tetrazole, thiophene, furan, imidazole,

In an advantageous embodiment according to the invention, the compoundsused as antischistosomal agents are compounds of formula (I) wherein

-   -   X₁, X₂, X₃ and X₄ represent all carbon atoms, with X₂ or X₃        optionally substituted by a halogen atom or a linear or branched        (C₁-C₄) alkoxy group,    -   the bond - - - - - between O in position 17 and X₁₀ represents        no bond and the bonds        between atoms C1/O18 and C4/O17 are double bonds, the bonds        between carbons in positions C1/C2 and C3/C4 are simple bonds,        the bond between carbons in positions C2/C3 is a double bond,        then R does not exist and    -   X₅ represents CO or CH₂ or CHOH,    -   X₆, X₇, X₈, X₉ and X₁₀ represent all carbon atoms with at least        one of X₆, X₇, X₈, X₉, optionally substituted by a substituent        selected from a halogen atom, a linear or branched (C₁-C₄)alkyl        group, a linear or branched (C₁-C₄)alkoxy group, —a        trifluoromethyl group, —a trifluoromethoxy group, —COOH, —CN,        —NO₂, a —NR₂R₃ with R₂ and R₃ representing each independently a        hydrogen atom, an amino protecting group selected from the group        comprising Boc group and (C₁-C₄)alkyl group, or R₂ and R₃        forming with the nitrogen atom which bears them a cyclic group        selected from the group comprising morpholine, piperidine, and        piperazine groups, said cyclic groups being optionally        substituted.

In another advantageous embodiment according to the invention, thecompounds used as antischistosomal agents are compounds of formula (I)wherein

X₁ represents a nitrogen atom and X₂, X₃ and X₄ carbon atoms, with atleast one of X₂, X₃ and X₄ being optionally substituted by a linear orbranched (C₁-C₄)alkyl group,

-   -   the bond - - - - - between O in position 17 and X₁₀ represents        no bond and the bonds        between atoms C1/O18 and C4/O17 are double bonds, the bonds        between carbons in positions C1/C2 and C3/C4 are simple bonds,    -   X₅ represents CH₂,    -   X₆, X₇, X₈, X₉ and X₁₀ represent all carbon atoms with at least        one of X₆, X₇, X₈, X₉ optionally substituted by a substituent        selected from a halogen atom, a linear or branched (C₁-C₄)alkoxy        group and—a trifluoromethyl group.

Some compounds are new and are also part of the invention.

Consequently another object of the invention are new compounds offormula (Ia):

wherein

-   -   either X₁, X₂, X₃ and X₄ represent all carbon atoms    -   either X₁ represents a carbon atom and one of X₂, X₃ and X₄        represents a nitrogen atom and the two others represent carbon        atoms,    -   either X₁ and X₄ represent each a nitrogen atom and X₂ and X₃        represent a carbon atom,    -   X₅ represents CO or CH₂ or CHOH,

X₆, X₇, X₈, X₉ and X₁₀ represent all carbon atoms or one of themrepresents a nitrogen atom and the four others are carbon atoms,

X₁, X₂, X₃, X₄, X₆, X₇, X₈, X₉ and X₁₀ when they are carbon atoms may besubstituted as disclosed above,

with the proviso than if X₁, X₂, X₃ and X₄ represent all carbon atoms orif X₁ represents a nitrogen atom, then at least one of X₆, X₇, X₈, X₉and X₁₀ represents a nitrogen atom.

Another aspect of the invention are new compounds responding to formula(Ia):

wherein

-   -   either X₁, X₂, X₃ and X₄ represent all carbon atoms    -   either X₁ represents a carbon atom and one of X₂, X₃ and X₄        represents a nitrogen atom and the two others represent carbon        atoms,    -   either X₁ and X₄ represent each a nitrogen atom and X₂ and X₃        represent a carbon atom,    -   X₅ represents CO or CH₂ or CHOH,

X₆, X₇, X₈, X₉ and X₁₀ represent all carbon atoms or one of themrepresents a nitrogen atom and the four others are carbon atoms,

X₁, X₂, X₃, X₄, X₆, X₇, X₈, X₉ and X₁₀ when they are carbon atoms may besubstituted as defined above,

with the proviso than if X₁, X₂, X₃ and X₄ represent all carbon atoms orif X₁ represents a nitrogen atom, then at least one of X₆, X₇, X₈, X₉and X₁₀ represents a nitrogen atom and if X1, X2, X3 and X4 allrepresent unsubstituted carbon atoms and X5 represents CH2 then neitherX7 nor X9 represents a nitrogen atom.

-   -   The second part of the above disclaimer is intended to exclude        the product code-named n^(o) 25 in the publication Journal of        Medicinal Chemistry 1991, Vol. 34, N° 1 p. 270.

In an advantageous embodiment, the compounds according to the inventionare selected from the group comprising:

wherein Z₁, Z₂, Z₃ et Z₄ represent each independently of the other,

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

X₆, X₇, X₈, X₉ and X₁₀ are as defined above, with the proviso that inthe compound of formula (Ia1) or of formula (Ia6) at least one of X₆,X₇, X₈, X₉ and X₁₀ represents a nitrogen atom.

In an other advantageous embodiment, the compounds according to theinvention are selected from the group comprising:

wherein Z₁, Z₂, Z₃ et Z₄ represent each independently of the other,

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

X₆, X₇, X₈, X₉ and X₁₀ are as defined above, with the proviso that inthe compound of formula (Ia1) or of formula (Ia6) at least one of X₆,X₇, X₈, X₉ and X₁₀ represents a nitrogen atom.

Another object of the invention are compounds of formula (Ib):

wherein

-   -   either X₁, X₂, X₃ and X₄ represent all carbon atoms,    -   or one of X₁, X₂, X₃ and X₄ represents a nitrogen atom and the        three others represent carbon atoms,    -   or X₁ and X₄ represent a nitrogen atom and X₂ and X₃ represent        carbon atoms,

X₅ represents CO or CH₂ or CHOH,

X₆, X₇, X₈, X₉ and X₁₀ represent all carbon atoms or one of X₆, X₇, X₈,X₉ represents a nitrogen atom and the four others are carbon atoms,

R represents a hydrogen atom, or an acetyl group,

X₁, X₂, X₃, X₄, X₆, X₇, X₈ and X₉ when they are carbon atoms may besubstituted as defined above.

Another object of the invention are compounds of formulas (Ia) and (Ib)and the pharmaceutically acceptable salts thereof for their use asdrugs, especially as antiparasitic agents to target blood-feedingparasites.

Another object of the invention is the use of compounds of formulas (I)in general and in particular (Ia), (Ia1) to (Ia6) (Ib) and (Ip) and thepharmaceutically acceptable salts thereof in therapy and prophylaxis.

The instant invention also provides a method for the prevention or thetreatment of parasitic disease due to blood-feedings parasites ofhumans, cattles and pets, in particular human diseases like malaria orschistosomasis comprising the administration to a patient in needthereof of a therapeutically effective amount of a compound of formula(I) as defined above.

In accordance with the invention, the compounds of formula (Ia), (Ia1)to (Ia6) (Ib) and (Ip) are useful in pharmaceutically acceptablecompositions. Thus another object of the invention are pharmaceuticallyacceptable composition comprising at least one compound selected fromcompounds of formula (Ia), (Ia1) to (Ia6), (Ip) and (Ib) and saltsthereof in combination with excipients and/or pharmaceuticallyacceptable diluents or carriers. Any conventional carrier material canbe utilized. The carrier material can be an organic or inorganic inertcarrier material, for example one that is suitable for oraladministration. Suitable carriers include water, gelatin, gum arabic,lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene-glycols, glycerine and petroleum jelly. Furthermore, thepharmaceutical preparations may also contain other pharmaceuticallyactive agents. Additional additives such as flavoring agents,preservatives, stabilizers, emulsifying agents, buffers and the like maybe added in accordance with accepted practices of pharmaceuticalcompounding. The pharmaceutical preparations can be made up in anyconventional form including a solid form for oral administration such astablets, capsules, pills, powders, granules, and rectal suppositories.The pharmaceutical preparations may be sterilized and/or may containadjuvants such as preservatives, stabilizers, wetting agents,emulsifiers, salts for varying the osmotic pressure and/or buffers.

The compositions of the invention can also be administered to a patientin accordance with the invention by topical (including transdermal,buccal or sublingual), or parenteral (including intraperitoneal,subcutaneous, intravenous, intradermal or intramuscular injection)routes.

The composition may comprise other active agents which may be one tothree other antimalarial agents selected from the group comprisingatovaquone, chloroquine, amodiaquine, mefloquine, ferroquine,artemisinin and the related peroxans from the pharmaceutical market likeartesunate, arteether and artemether, menadione, methylene blue,proguanil, cycloguanil, chlorproguanil, pyrimethamine, primaquine,piperaquine, fosmidomycin, halofantrine, dapsone, trimethoprim,sulfamethoxazole, sulfadoxine, ascorbate, for a simultaneous, separatedor sequential, or administration.

The composition may comprise other active agents which may be one tothree other antischistosomal agents selected from the group comprisingpraziquantel, atovaquone, artemisinin and the related peroxans from thepharmaceutical market like artesunate, arteether and artemether,oxamniquine, dehydroemetine dichlorhydrate, emetine camsilate, emetinechlorhydrate, oltipraz, hycanthone mesilate, lucanthone chlorhydrate,ferroquine, ascorbate, for a simultaneous, separated or sequential, oradministration.

A further object of the invention is a process for preparing compoundsof formula (I):

wherein:

-   -   either X₁, X₂, X₃ and X₄ represent all carbon atoms,    -   either one of X₁, X₂, X₃ and X₄ represents a nitrogen atom and        the three others represent carbon atoms,    -   either X₁ and X₄ represent a nitrogen atom and X₂ and X₃ both        represent carbon atoms,    -   the bond - - - - - between O in position 17 and X₁₀ represents        no bond or a single bond,    -   the bond        represents either a single bond or a double bond,

X₅ represents CO or CH₂ or CHOH,

X₆, X₇, X₈, X₉ and X₁₀ represent all carbon atoms or one of themrepresents a nitrogen atom and the four others are carbon atoms,

with the proviso that when the bond - - - - - between O17 and X₁₀represents a single bond, then the bonds

between atoms in positions C1/O18 and C4/O17 are single bonds, the bondsbetween carbons in positions C1/C2 and C3/C4 are double bonds, the bondbetween carbons in positions C2/C3 is a simple bond, and R represents ahydrogen atom or an acetyl group and X₁₀ is not a nitrogen atom and

X₁, X₂, X₃ and X₄ when they are carbon atoms being optionallysubstituted by:

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

X₆, X₇, X₈, X₉, X₁₀—except when atoms O17 and X₁₀ are bound by a simplebond and X₁₀ is a quarternary carbon atom—being optionally substitutedby:

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,    -   a difluoromethoxy group,    -   a difluoromethyl group,    -   —COOH,    -   —COO(C₁-C₄)alkyl group,    -   —CONR₁(CH₂)_(m)CN, with R₁ being a hydrogen atom or a linear or        branched (C₁-C₄)alkyl group and m=1, 2 or 3,    -   —CSNR₁(CH₂)_(m)CN, with R₁ being a hydrogen atom or a linear or        branched (C₁-C₄)alkyl group m=1, 2 or 3,    -   —CONR₁Het with R₁ being a hydrogen atom or a linear or branched        (C₁-C₄)alkyl group, Het representing a pyridine-2-yl group, said        group optionally substituted by an amino group in -6 or by a        —CONH₂ group in -5,    -   —NO₂,    -   —CN,    -   —NR₂R₃ with R₂ and R₃ representing each independently a hydrogen        atom, an amino protecting group selected from the group        comprising Boc group and (C₁-C₄)alkyl group, or R₂ and R₃        forming with the nitrogen atom which bears them a cyclic group        selected from the group comprising morpholine, piperidine, and        piperazine groups, said cyclic groups being optionally        substituted.    -   an aryl group or an aryl group substituted by one or several        substituents selected from the group comprising a (C₁-C₄)alkyl        group, a —NO₂ group, a —COOR₄ with R₄ selected from a hydrogen        atom and a linear or branched (C₁-C₄)alkyl group, a —NR₅R₆ with        R₅ and R₆ independently selected from the group comprising a        hydrogen atom and a linear or branched (C₁-C₄)alkyl group,    -   a heterocyclic group selected from the group comprising        morpholinyl group or piperazinyl group, each of said group being        optionally substituted by one or several substituents selected        from the group comprising a linear or branched (C₁-C₄)alkyl        group, —COOCH₂CH₃, or a group

said process comprising the step of reacting a compound of formula (II)

wherein X₁, X₂, X₃ and X₄ are as defined above

with a compound of formula (III)

wherein X₅ represents CO or CH₂, X₆, X₇, X₈, X₉ and X₁₀ are as definedabove

in a Kochi-Anderson reaction to give a compound of formula (Ia)

A further object of the invention is a proces further comprising thestep of submitting a compound of formula (Ia) as obtained above

wherein X₁, X₂, X₃, X₄, X₅, X₇, X₈, X₉ are, as defined above and atleast one of X₆ and X₁₀ bears a leaving group selected from the groupcomprising F, Cl, Br or OMe, to a reduction into hydronaphthoquinonefollowed by a intramolecular nucleophilic aromatic substitution to givea compound of formula (Ib)

wherein X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉ and X₁₀ are, as definedabove.

The invention has also as an object a process for preparing compounds offormula (Ia1)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₁, Z₂, Z₃and Z₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa1)

wherein Z₁, Z₂, Z₃ and Z₄ are as defined above, is prepared by treatinga compound of formula (IV)

with a base in a solvent like for example toluene in the presence of analkylformate like ethylformate to yield a compound of formula (V)

which is oxidised for example by2,3-dichloro-5,6-dicyano-1,4-benzoquinone (or DDQ) in a solvent likedioxane to give a compound of formula (VI)

which is treated with ethylchloroformate in a solvent like for exampletetrahydrofurane (THF) in the presence of a base like for exampletriethylamine and of sodium tetrahydroboride to give a compound offormula (VII)

which is treated by oxidation for example with phenyliodonium diacetate(PIDA) or [Bis(trifluoroacetoxy)iodo]benzene (PIFA) or Oxone®, in asolvent to yield a compound of formula (IIa1), said compound of formula(IIa1) being reacted in a Kochi-Anderson reaction with a compound offormula (III) as defined above to yield a compound of formula (Ia1).

The invention has also as an object a process for preparing compounds offormula (Ia1)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₁, Z₂, Z₃and Z₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa1)

wherein Z₁, Z₂, Z₃ and Z₄ are as defined above is prepared by treating acompound of formula (VIII)

with bromine in an acidic medium to yield a compound of formula (IX)

which is submitted to a nucleopilic substitution to yield a compound offormula (X)

with Z₅ representing a xanthate group, like S(S)OEt, S(S)OMe or S(S)OPr

which is submitted to a radical reaction to yield a compound of formula(XI)

which is cyclised into a tetralone of formula (XII)

which is deshydrated to give a compound of formula (VII)

which is treated by oxidation for example with phenyliodonium diacetate(PIDA) or [Bis(trifluoroacetoxy)iodo]benzene (PIFA) or Oxone® in asolvent like a mixture of water and acetonitrile to yield a compound offormula (IIa1) said compound of formula (IIa1) being reacted in aKochi-Anderson reaction with a compound of formula (III) as definedabove to yield a compound of formula (Ia1).

The invention has also as an object a process for preparing compounds offormula (Ia2)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₁, Z₃ andZ₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa2)

wherein Z₁, Z₃ and Z₄ are as defined above, is prepared by reacting acompound of formula (XIII)

with a compound of formula (XVI)

wherein Z₁, Z₃ and Z₄ are as defined above,

to yield a compound of formula (IIa2), said compound of formula (IIa2)being reacted in a Kochi-Anderson reaction with a compound of formula(III) as defined above to yield a compound of formula (Ia2).

The invention has also as an object a process for preparing compounds offormula (Ia3)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₁, Z₃ andZ₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa3)

wherein Z₁, Z₂ and Z₄ are as defined above is prepared by reacting acompound of formula (XIV)

with a compound of formula (XVII)

wherein Z₁, Z₃ and Z₄ are as defined above,

to yield a compound of formula (IIa3), said compound of formula (IIa3)being reacted in a Kochi-Anderson reaction with a compound of formula(III) as defined above to yield a compound of formula (Ia3).

The invention has also as an object a process for preparing compounds offormula (Ia4)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₂, Z₃ andZ₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa4)

is prepared by reacting a compound of formula (XIV)

with a compound of formula (XVIII)

wherein Z₂, Z₃ and Z₄ are as defined above, said compound of formula(IIa4) being reacted in a Kochi-Anderson reaction with a compound offormula (III) as defined above to yield a compound of formula (Ia4).

The invention has also as an object a process for preparing compounds offormula (Ia6)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₂, Z₃ andZ₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa6)

wherein Z₂, Z₃ and Z₄ are as defined above is prepared by reacting acompound of formula (XIII)

with a compound of formula (XVIII)

wherein Z₂, Z₃ and Z₄ are as defined above, said compound of formula(IIa6) being reacted in a Kochi-Anderson reaction with a compound offormula (III) as defined above to yield a compound of formula (Ia6).

The invention has also as an object a process for preparing compounds offormula (Ia5)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined before and Z₂ and Z₃which are the same are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa5)

wherein Z₂ et Z₃ which are the same are as defined above,

is prepared by reacting a compound of formula (XIX)

wherein Z₂ and Z₃ which are the same are as defined above,

with a compound of formula (XX)

said compound of formula (IIa5) being reacted in a Kochi-Andersonreaction with a compound of formula (III) as defined above to yield acompound of formula (Ia5).

The invention has also as an object a process for preparing a compoundof formula (Ib1)

wherein

X₅ is CO, X₆, X₇, X₈, X₉, X₁₀ and R are as defined above

wherein a 2-bromo-1,4-dimethoxy-3-methylnaphtalene of formula (XXI)

is reacted with a compound of formula (XXII)

wherein X₅ is CO, X₇, X₈, X₉, are as defined before, X₁₀ and X₆ bear aleaving group selected from the group comprising F, Cl, Br and OMe andZ₅ represents an halogen atom or an alkoxy group, in particular amethoxy group.

in presence of a lithium base derivative to yield a compound of formula(XXIII)

which is treated with BBr₃ and a base like K₂CO₃ medium to give acompound of

Another object of the invention is a process for preparing compounds offormula (I):

wherein:

-   -   either X₁, X₂, X₃ and X₄ represent all carbon atoms,    -   either one of X₁, X₂, X₃ and X₄ represents a nitrogen atom and        the three others represent carbon atoms,    -   either X₁ and X₄ represent a nitrogen atom and X₂ and X₃ both        represent carbon atoms,

the bond - - - - - between O in position 17 and X₁₀ represents no bondor a single bond,

the bond

represents either a single bond or a double bond,

X₅ represents CO or CH₂ or CHOH,

X₆, X₇, X₈, X₉ and X₁₀ represent all carbon atoms or one of themrepresents a nitrogen atom and the four others are carbon atoms,

i) when the bond - - - - - between O17 and X₁₀ represents a single bond,then the bonds

between atoms in positions C1/O18 and C4/O17 are single bonds, the bondsbetween carbons in positions C1/C2 and C3/C4 are double bonds, the bondbetween carbons in positions C2/C3 is a simple bond, and R represents ahydrogen atom or an acetyl group and X₁₀ is not a nitrogen atom and

ii) when the bond - - - - - between O17 and X₁₀ represents no bond, thenR does not exist and the bonds

between atoms C1/O18 and C4/O17 are double bonds, the bonds betweencarbons in positions C1/C2 and C3/C4 are simple bonds, the bond betweencarbons in positions C2/C3 is a double bond, and

X₁, X₂, X₃ and X₄ when they are carbon atoms being optionallysubstituted by:

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

X₆, X₇, X₈, X₉, X₁₀—except when atoms O17 and X₁₀ are bound by a simplebond and X₁₀ is a quarternary carbon atom—being optionally substitutedby:

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,    -   a difluoromethoxy group,    -   a difluoromethyl group,    -   —COOH,    -   —COO(C₁-C₄)alkyl group,    -   —CONR₁(CH₂)_(m)CN, with R₁ being a hydrogen atom or a linear or        branched (C₁-C₄)alkyl group and m=1, 2 or 3,    -   —CSNR₁(CH₂)_(m)CN, with R₁ being a hydrogen atom or a linear or        branched (C₁-C₄)alkyl group m=1, 2 or 3,    -   —CONR₁Het with R₁ being a hydrogen atom or a linear or branched        (C₁-C₄)alkyl group, Het representing a pyridine-2-yl group, said        group optionally substituted by an amino group in -6 or by a        —CONH₂ group in -5,    -   —NO₂,    -   —CN,    -   —NR₂R₃ with R₂ and R₃ representing each independently a hydrogen        atom, an amino protecting group selected from the group        comprising Boc group and (C₁-C₄)alkyl group, or R₂ and R₃        forming with the nitrogen atom which bears them a cyclic group        selected from the group comprising morpholine, piperidine and        piperazine groups, said cyclic groups being optionally        substituted.    -   an aryl group or an aryl group substituted by one or several        substituents selected from the group comprising a (C₁-C₄)alkyl        group, a —NO₂ group, a —COOR₄ with R₄ selected from a hydrogen        atom and a linear or branched (C₁-C₄)alkyl group, a —NR₅R₆ with        R₅ and R₆ independently selected from the group comprising a        hydrogen atom and a linear or branched (C₁-C₄)alkyl group,    -   a heterocyclic group selected from the group comprising        morpholinyl group or piperidinyl or piperazinyl group, each of        said group being optionally substituted by one or several        substituents selected from the group comprising a linear or        branched (C₁-C₄)alkyl group, —COOCH₂CH₃, or a group

said process comprising the step of reacting a compound of formula (II)

wherein X₁, X₂, X₃ and X₄ are as defined above

with a compound of formula (III)

wherein X₅ is CO or CH₂, X₆, X₇, X₈, X₉ and X₁₀ are as defined above

in a Kochi-Anderson reaction to give a compound of formula (Ia)

The compounds of formula (Ia) are polysubstituted naphthoquinones andare a subgroup of compounds of formula (I).

In an advantageous embodiment according to the invention, the processfurther comprises the step of submitting a compound of formula (Ia)

wherein X₁, X₂, X₃, X₄, X₅, X₇, X₈, X₉ are as defined above and at leastone of X₆ and X₁₀ bears a leaving group selected from the groupcomprising F, Cl, Br or OMe, to a reduction into hydronaphthoquinonefollowed by a intramolecular nucleophilic aromatic substitution to givea compound of formula (Ib)

Compounds of formula (Ib) are called benz[c]xanthen-7-ones (shortened asbenzxanthones) and are a subgroup of compounds of formula (I).

In another embodiment of the invention the process is used for preparingcompounds of formula (Ia1)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₁, Z₂, Z₃and Z₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa1)

wherein Z₁, Z₂, Z₃ and Z₄ are as defined above, is prepared by treatinga compound of formula (IV)

with a base in a solvent like for example toluene in the presence of analkylformate like ethylformate to yield a compound of formula (V)

which is oxidised for example by2,3-dichloro-5,6-dicyano-1,4-benzoquinone (or DDQ) in a solvent likedioxane to give a compound of formula (VI)

which is treated with ethylchloroformate in a solvent like for exampletetrahydrofurane (THF) in the presence of a base like for exampletriethylamine and of sodium tetrahydroboride to give a compound offormula (VII)

which is treated by oxidation for example with phenyliodonium diacetate(PIDA) or [Bis(trifluoroacetoxy)iodo]benzene (PIFA) or Oxone®, in asolvent to yield a compound of formula (IIa1), said compound of formula(IIa1) being reacted in a Kochi-Anderson reaction with a compound offormula (III) as defined above to yield a compound of formula (Ia1).

In another embodiment of the invention the process is used for preparingcompounds of formula (Ia1)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₁, Z₂, Z₃and Z₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa1)

wherein Z₁, Z₂, Z₃ and Z₄ are as defined above is prepared by treating acompound of formula (VIII)

with bromine in an acidic medium to yield a compound of formula (IX)

which is submitted to a nucleopilic substitution to yield a compound offormula (X)

with Z₅ representing a xanthate group, like S(S)OEt, S(S)OMe or S(S)OPr

which is submitted to a radical reaction to yield a compound of formula(XI)

which is cyclised into a tetralone of formula (XII)

which is deshydrated to give a compound of formula (VII)

which is treated by oxidation for example with phenyliodonium diacetate(PIDA) or [Bis(trifluoroacetoxy)iodo]benzene (PIFA) or Oxone® in asolvent like a mixture of water and acetonitrile to yield a compound offormula (IIa1), said compound of formula (IIa1) being reacted in aKochi-Anderson reaction with a compound of formula (III) as definedabove to yield a compound of formula (Ia1). This route is called thepropiophenone route.

In another embodiment of the invention the process is used for preparingcompounds of formula (Ia1)

wherein X5 X6, X7, X8, X9 and X10 are as defined above and Z1, Z2, Z3and Z4 are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C1-C4)alkyl group,    -   a linear or branched (C1-C4)alkoxy group,    -   a thio(C1-C4)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa1)

wherein Z₁, Z₂, Z₃ and Z₄ are as defined above is prepared by treating acompound of formula (XIII)

or a compound of formula (XIV)

with a compound of formula (XV), pyridine and DDQ or SiO₂

wherein Z₁, Z₂, Z₃ and Z₄ are as defined above,

to yield a compound of formula (IIa1), said compound of formula (IIa1)being reacted in a Kochi-Anderson reaction with a compound of formula(III) as defined above to yield a compound of formula (Ia1). This routeis called the Diels-Alder route.

In another embodiment of the invention the process is used for preparingcompounds of formula (Ia2)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₁, Z₃ andZ₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa2)

wherein Z₁, Z₃ and Z₄ are as defined above, is prepared by reacting acompound of formula (XIII)

with a compound of formula (XVI)

wherein Z₁, Z₃ and Z₄ are as defined above,

to yield a compound of formula (IIa2), said compound of formula (IIa2)being reacted in a Kochi-Anderson reaction with a compound of formula(III) as defined above to yield a compound of formula (Ia2).

Another object of the invention is a process for preparing compounds offormula (Ia3)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₁, Z₃ andZ₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa3)

wherein Z₁, Z₂ and Z₄ are as defined above is prepared by reacting acompound of formula (XIV)

with a compound of formula (XVII)

wherein Z₁, Z₃ and Z₄ are as defined above,

to yield a compound of formula (IIa3), said compound of formula (IIa3)being reacted in a Kochi-Anderson reaction with a compound of formula(III) as defined above to yield a compound of formula (Ia3).

In another embodiment of the invention, the process is used forpreparing compounds of formula (Ia4)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₂, Z₃ andZ₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa4)

is prepared by reacting a compound of formula (XIV)

with a compound of formula (XVIII)

wherein Z₂, Z₃ and Z₄ are as defined above, said compound of formula(IIa4) being reacted in a Kochi-Anderson reaction with a compound offormula (III) as defined above to yield a compound of formula (Ia4).

In another embodiment of the invention, the process is used forpreparing compounds of formula (Ia6)

corresponding to a compound of formula (Ia) wherein X₁ is a nitrogenatom, X₂, X₃ and X₄ are carbon atoms and

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined above and Z₂, Z₃ andZ₄ are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa6)

wherein Z₂, Z₃ and Z₄ are as defined above is prepared by reacting acompound of formula (XIII)

with a compound of formula (XVIII)

wherein Z₂, Z₃ and Z₄ are as defined above, said compound of formula(IIa6) being reacted in a Kochi-Anderson reaction with a compound offormula (III) as defined above to yield a compound of formula (Ia6).

In another embodiment of the invention, the process is used forpreparing compounds of formula (Ia5)

wherein X₅, X₆, X₇, X₈, X₉ and X₁₀ are as defined before and Z₂ and Z₃which are the same are selected from the group comprising

-   -   a hydrogen atom,    -   a halogen atom,    -   a hydroxy group,    -   a triflate group,    -   a phosphate group,    -   a linear or branched (C₁-C₄)alkyl group,    -   a linear or branched (C₁-C₄)alkoxy group,    -   a thio(C₁-C₄)alkoxy group,    -   a pentafluorosulfanyl group,    -   —SCF₃    -   —SCH₂F,    -   a trifluoromethyl group,    -   a trifluoromethoxy group,

wherein a compound of formula (IIa5)

wherein Z₂ et Z₃ which are the same are as defined above,

is prepared by reacting a compound of formula (XIXI)

wherein Z₂ and Z₃ which are the same are as defined above,

with a compound of formula (XIII)

said compound of formula (IIa5) being reacted in a Kochi-Andersonreaction with a compound of formula (III) as defined above to yield acompound of formula (Ia5).

In another embodiment of the invention, the process is used forpreparing a compound of formula (Ib1)

wherein

X₅ is CO, X₆, X₇, X₈, X₉, X₁₀ and R are as defined before

wherein a 2-bromo-1,4-dimethoxy-3-methylnaphtalene of formula (XXI)

is reacted with a compound of formula (XXII)

wherein X₅ is CO, X₇, X₈, X₉, are as defined before, X₁₀ and X₆ bear aleaving group selected from the group comprising F, Cl, Br and OMe andZ₅ represents an halogen atom or an alkoxy group, in particular amethoxy group.

in presence of a lithium base derivative to yield a compound of formula(XXIII)

which is treated with BBr₃ and a base like K₂CO₃ medium to give acompound of formula (Ib1).

The following examples 1 to 20 and the FIGS. 1 to 5 are intended asillustrations of a few embodiments of the invention.

FIG. 1 illustrates the antimalarial activity ofpolysubstituted-naphthoquinones, azanaphthoquinones, xanthones andbenzxanthone derivatives according to the invention measured accordingto example 19 against P. falciparum Dd2 and 3D7 strains, both in theradioactive ³H hypoxanthine incorporation assay and in the SYBRgreenassay. In the table, the asterisks (*, **, ***, ****) referred to thevalues determined for antimalarial chloroquine used as key control inthree disctinct experiments (*, **, ***, ****). The cells of the tablewith grey background show structures of compounds disclosed in theinternational application WO 2009/118327 and used as references in theantimalarial assays.

FIG. 2 illutrates the putative cascade of redox reactions generated insitu in the blood-feeding parasites responsible for the antiparasiticaction of compounds (simplified in the structure) described in thepresent application.

FIG. 3 illutrates profound morphological changes induced by two3-benzylmenadione derivatives LJ83K (right) and LJ81K despite the weakTGR inhibitory capabilities.

FIG. 4 illustrates the antischistosomal effects of derivatives describedin the invention measured according to example 20 against S. mansoniworms in cultures. D=100% dead, except when given with a number (% D)which indicated the percentage of dead worms. Addition of hemoglobin(Hb) was applied in order to favor drug metabolism throughheme-catalyzed oxidations. Addition of red blood cells (RBC) was appliedin order to favor drug metabolism through hemoglobin digestion andheme-catalyzed oxidations. In the table, the term “50/10/5” means thatthe compounds were tested at 50 μM, 10 μM and 5 μM.

FIG. 5 illustrates the antischistosomal activity of LJ83K described inthe invention measured according to example 20 against S. mansoniworms-infected mice. All injections were ip: the first injection wascarried out six weeks post-infection, the second was performed two dayslater. Perfusion was 7 days after the second injection date. LJ83K(=P_TM58) was injected twice at 33 mg/kg.

EXAMPLE 1 General Procedure for Alpha-Formylation of Tetralone IV into V

It is based on the work disclosed by B. C. Pearce, R. A. Parker, M. E.Deason, D. D. Dischino, E. Gillepsie, A. A. Qureshi, K. Volk, J. J. KimWright J. Med. Chem. 1994, 37, 526-541.

A mixture of tetralone IV in toluene (1 eq, 0.45 mmol·mL⁻¹) and ethylformate (2.0 eq) was prepared. The solution was cooled to −78° C. underArgon and mechanically stirred while potassium tert-butoxide (2.0 eq)was added in portions: the solution became milky and pinky. The solutionwas warmed to −5° C. until TLC monitoring (petroleumether/Et₂O: 3/1)indicated the completion of the reaction. The solution was quenched with10% HCl (the pink solution disappeared) and the mixture extracted withEt₂O. The organic phases were dried (brine, MgSO₄) and concentrated invacuo to yield alpha-formyl tetralone (usually as solid compound).

Note: usually the product does not need to be further purified and canbe directly engaged in the next step.

1.1. 2-(hydroxymethylene)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one

Yield: >98% (light brown solid)

¹H NMR (200 MHz, CDCl₃): δ=2.51 (t, 2H, J=7.3 Hz), 2.82 (t, 2H, J=7.3Hz), 3.82 (s, 3H), 6.68 (d, 1H, J=2.4 Hz), 6.82 (dd, 1H, J=8.6 Hz, 2.4Hz), 7.91 (d, 1H, J=8.6 Hz), ppm

The spectroscopic and physical data were identical to those reported inthe literature (S. H. Kim, J. R. Gunther, J. A. Katzenellenbogen Org.Lett. 2008, 10, 4931-4934).

1.2. 2-(hydroxymethylene)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one

The compound was prepared in the conditions disclosed in 1.1.

Yield: 87% yellow powder

¹H NMR (300 MHz, CDCl₃): δ=2.55-2.50 (m, 2H), 2.82-2.78 (m, 2H), 3.82(s, 3H), 6.99 (dd, J=8.3 Hz, J=2.8 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.45(d, J=2.8 Hz, 1H), 8.11 (d, J=5.4 Hz, 1H), ppm

¹³C NMR (75 MHz, CDCl₃): δ=23.2 (CH₂), 27.9 (CH₂), 55.5 (OCH₃), 108.9(CH), 109.4 (CH), 120.3 (CH), 129.1 (CH), 130.1 (C_(quat)), 130.1(C_(quat)), 132.5 (C_(quat)), 134.1 (C_(quat)), 158.7 (C_(quat)), 175.5(CH), 183.2 (C═O) ppm

The spectroscopic and physical data were identical to those reported inthe literature. (C. Bilger, P. Demerseman, R. Royer Eur. J. Med. Chem.1987, 22, 363-5).

1.3. 2-(hydroxymethylene)-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one

Yield: >98% (light brown solid)

¹H NMR (300 MHz, CDCl₃): δ=2.38 (t, J=7.1 Hz, 2H), 2.86 (t, J=7.1 Hz,2H), 3.95 (s, 3H), 3.96 (s, 3H), 6.68 (s, 1H), 6.82 (s, 1H), 7.78 (d,J=7.0 Hz, 1H), ppm

¹³C NMR (75 MHz, CDCl₃): δ=23.7 (CH₂), 28.97 (CH₂), 56.1 (2×OCH₃), 108.2(C_(quat)), 108.3 (CH), 110.3 (CH), 124.9 (C_(quat)), 137.0 (C_(quat)),148.1 (C_(quat)), 153.24 (C_(quat)), 169.7 (CH), 186.1 (C═O) ppm

1.4. 2-(hydroxymethylene)-7-fluor-3,4-dihydronaphthalen-1(2H)-one

The compound was prepared in the conditions disclosed in 1.1.

Yield: 99% yellow powder

¹H NMR (300 MHz, CDCl₃): δ=2.59 (t, J=7.1 Hz, 2H), 2.88 (t, J=7.1 Hz,2H), 7.11-7.24 (m, 2H), 7.64 (d, J=9.1 Hz, J=2.8 Hz, 1H), 8.27 (d, J=5.4Hz, 1H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=22.7 (CH₂), 28.0 (CH₂), 108.5 (C_(quat))111.7 (d, J=22.8 Hz, CH), 119.7 (d, J_(C-F)=19.4 Hz, CH), 129.5 (d,J_(C-F)=7.3 Hz, CH), 133.2 (d, J=7.2 Hz, C_(quat)), 137.0 (d,J_(C-F)=3.2 Hz, C_(quat)), 161.8 (d, J_(C-F)=245.0 Hz, C_(quat)), 177.6(CH), 180.8 (C═O) ppm.

EXAMPLE 2 General Procedure for Aromatisation of α-Formyl-Tetralone (V)into (VI)

It is based on the work disclosed by S. H. Kim, et al. (cited above).

To a solution of tetralone (V) in dioxanne (1.0 eq, 0.2 mmol·mL⁻¹) wasadded 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (or DDQ) (1.0 eq) atroom temperature. A white precipitate appeared rapidly. After completionof the reaction (TLC monitoring), the white precipitate was removed byfiltration. The filtrate was concentrated under reduced pressure.

The crude was purified by column chromatography (silica gel, eluantcyclohexane/Et₂O:3/1).

2.1. 1-hydroxy-6-methoxy-2-naphthaldehyde

Yield: 72-75%

¹H NMR (200 MHz, CDCl₃): δ=3.96 (s, 3H), 7.09 (d, 1H, J=2.6 Hz), 7.18(dd, 1H, J=9.2 Hz, 2.6 Hz), 7.26 (d, 1H, J=8.8 Hz), 7.45 (d, 1H, J=8.8Hz), 8.35 (d, 1H, J=9.2 Hz), 9.90 (s, 1H), 12.70 (s, 1H) ppm

The spectroscopic and physical data were identical to those reported inthe literature. (S. H. Kim, et al. (cited above)

2.2. 1-hydroxy-7-methoxy-2-naphthaldehyde

Yield: 83% yellow powder

¹H NMR (300 MHz, CDCl₃): δ=12.40 (s, 1H), 9.81 (s, 1H), 7.56-7.51 (m,2H), 7.20-7.10 (m, 3H), 3.81 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=55.5 (OCH₃), 102.1 (CH), 114.6 (C_(quat)),119.3 (CH), 123.3 (CH), 124.3 (CH), 125.5 (C_(quat)), 129.1 (CH), 132.9(C_(quat)), 158.0 (C_(quat)), 160.5 (C_(quat)), 190.6 (C═O) ppm.

The spectroscopic and physical data were identical to those reported inthe literature (C. Bilger, et al, cited above).

2.3. 1-hydroxy-6,7-methoxy-2-naphthaldehyde

Yield: 73%

¹H NMR (300 MHz, CDCl₃): δ=3.99 (s, 3H), 4.00 (s, 3H), 7.05 (s, 1H),7.24 (AB system, J=8.7 Hz, Δν=30.1 Hz, 2H), 7.56 (s, 1H), 9.90 (s, 1H),12.55 (s, 1H) ppm

¹³C NMR (75 MHz, CDCl₃: δ=56.0 (OCH₃), 56.1 (OCH₃), 102.7 (CH), 106.4(CH), 113.5 (C_(q)), 118.0 (CH), 119.6 (C_(q)), 125.6 (CH), 134.7(C_(q)), 149.4 (C_(q)), 153.1 (C_(q)), 160.4 (C_(q)) 195.9 (C═O) ppm.

2.4. 1-hydroxy-7-fluor-2-naphthaldehyde

Yield: 87% yellow powder

¹H NMR (300 MHz, CDCl₃): δ=12.54 (s, 1H), 10.01 (s, 1H), 8.04 (dd, J=8.9Hz J=2.7 Hz) 7.80 (dd, J=8.9 Hz, J=5.4 Hz, 1H), 7.50-7.38 (m, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=108.2 (d, J_(C-F)=22.9 Hz, CH), 114.6(C_(q)), 119.2 (CH) 125.5 (d, J_(C-F)=8.8 Hz, C_(quat)), 125.8 (d,J_(C-F)=2.6 Hz, CH) 130.0 (CH), 130.1 (CH), 134.3 (d, J=1.5 Hz,C_(quat)), 160.8 (d, J=247.0 Hz, C_(quat)), 160.9 (d, J=1.5 Hz,C_(quat)), 196.4 (C═O) ppm.

EXAMPLE 3 General Procedure for Reduction of 2-formyl-1-naphtols VI intoVII

It is based on the work disclosed by N. Minami & S. Kijima Chem. Pharm.Bull. 1979, 27, 1490-1494.

To a solution of 2-formyl-1-naphtol in tetrahydrofuran (1.0 eq, 1mmol·mL⁻¹) was added triethylamine (1.2 eq). The solution was cooled to0° C. and then ethyl chloroformate (1.2 eq) was added over a period of30 min. The solution was left under stirring during 30-60 min (whiteprecipitates formation). The precipitates (triethylamine hydrochloride)were removed by filtration and washed with tetrahydrofuran (twice lessthan the amount used for the reaction). To the combined filtrates wereadded, at 5-15° C., an aqueous solution of NaBH₄ (4.0 eq, 2.6 M). Whenthe addition was completed, the reaction mixture was stirred at roomtemperature for 1-2 h, then diluted with water. The solution was cooledto 0° C. and made acidic by the slow addition of aqueous HCl (10%)(FROZING!). The aqueous solution was extracted with Et₂O. The organicphases were washed with dilute solution of NaOH (10%), dried (brine,MgSO₄) and concentrated in vacuo to yield methylnaphtol (usually as asolid or an oil which crystallized on standing).

Note: usually the product does not need to be further purified and canbe directly engaged in the next step.

3.1. 6-methoxy-2-methylnaphthalen-1-ol

Yield: 70%

This compound was reported in literature but was not described: Nowicki,Alexander W.; Turner, Alan B. Chemistry & Industry (London, UnitedKingdom) 1981, 14, 501-2.

¹H NMR (300 MHz, CD₂Cl₂): δ=2.37 (s, 3H), 3.90 (s, 3H), 5.19 (s, 10H),7.11 (m, 2H), 7.24 (AB system, J=8.1 Hz, Δν=17.1 Hz, 2H), 8.03 (d, J=9.8Hz, 1H) ppm

¹³C NMR (75 MHz, CD₂Cl₂): δ=15.7 (CH₃), 55.8 (OCH₃), 106.2 (CH), 114.8(C_(q)), 118.3 (CH), 119.5 (CH), 120.1 (C_(q)), 123.2 (CH), 130.3 (CH),135.3 (C_(q)), 149.4 (C_(q)), 158.1 (C_(q)) ppm

MS (EI): m/z (%): 188.1 ([M]⁺, 100), 145.0 (83), 115.0 (62), 189.1([M+H]⁺, 15)

3.2. 7-methoxy-2-methylnaphthalen-1-ol

Yield: 66% yellow powder

¹H NMR (300 MHz, CDCl₃): δ=7.65 (d, J=9.0 Hz, 1H), 7.42 (d, J=2.6 Hz,1H), 7.30 (d, J=8.4 Hz, 1H), 7.10-7.06 (m, 1H), 3.93 (s, 3H), 2.38 (s,3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=157.5 (C_(q)); 147.6 (C_(q)); 129.2 (CH);129.0 (C_(q)) 126.5 (CH); 125.2 (C_(q)); 120.0 (CH); 118.2 (CH); 116.7(C_(q)); 99.5 (CH); 55.4 (—OCH₃); 15.75 (CH₃) ppm.

3.3. 6,7-dimethoxy-2-methylnaphthalen-1-ol

Yield: 68% (yellow powder)

¹H NMR (300 MHz, CDCl₃): δ=2.37 (s, 3H), 3.90 (s, 3H), 5.19 (s, 10H),7.11 (m, 2H), 7.24 (AB system, J=8.1 Hz, Δν=17.1 Hz, 2H), 8.03 (d, J=9.8Hz, 1H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=15.58 (CH₃), 55.8 (OCH₃), 55.9 (OCH₃), 100.3(CH), 106.2 (CH), 114.7 (C_(q)), 118.7 (CH), 119.6 (C_(q)), 127.2 (CH),129.3 (C_(q)), 147.8 (C_(q)), 149.1 (C_(q)), 149.2 (C_(q)) ppm.

3.4. 7-fluor-2-methylnaphthalen-1-ol

Yield: 72% yellow powder

¹H NMR (300 MHz, CDCl₃): δ=7.90-7.36 (m, 1H), 7.29 (AB system, J=8.5 Hz,Δν=50.7 Hz, 2H) 7.24-7.17 (m, 1H), 2.41 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=162.2 (C_(q)), 148.3 (d, J_(C-F)=5.7 Hz,C_(q)), 130.4 (C_(q)), 130.0 (d, J_(C-F)=8.9 Hz, CH), 128.2 (d,J_(C-F)=2.7 Hz, CH), 125.2 (d, J_(C-F)=8.6 Hz, C_(q)), 120.0 (d,J_(C-F)=1.1, CH), 117.3 (C_(q)), 115.7 (d, J_(C-F)=25.2 Hz, CH), 105.1(d, J_(C-F)=22.4, CH), 15.7 (CH₃) ppm.

EXAMPLE 4 General Procedure for Oxidation of Methylnaphtols VII intoMenadiones Ia1

It is based on the work from P. Bachu, J. Sperry, M. A. BrimbleTetrahedron 2008, 64, 3343-3350

To a stirred solution of naphtol (5.8 mmol, 1 eq) in acetonitrile (70mL) and water (30 mL) at −5° C. was added[bis(trifluoroacetoxy)iodo]benzene (12.1 mmol, 2.1 eq) portionwise over20-30 nm. After stirring for 30 nm at −5° C., the reaction mixture wasstirred at RT for 1 h. Saturated NaHCO₃ solution was added to thereaction orange mixture and the reaction mixture extracted with Et₂O(3×120 mL). The combined organic extracts were washed with brine anddried over anhydrous MgSO₄. The crude was purified by flashchromatography on silica gel (eluant: hexanes/Et₂O).

4.1. 6-methoxy-2-methylnaphthalene-1,4-dione

Yield: 60-65%

This compound was shortly described in Sidhu et al. Indian Journal ofChemistry 1968, 6, 681-91

m.p. 146-148° C. (Et₂O)

¹H NMR (300 MHz, CDCl₃): δ=2.17 (d, J=1.6 Hz, 3H), 3.93 (s, 3H), 6.78(d, J=1.6 Hz, 1H), 7.17 (dd, J=8.6 Hz, J=2.7 Hz, 1H), 7.47 (d, J=2.7 Hz,1H), 8.02 (d, J=8.6 Hz, 1H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=16.5 (CH₃), 55.9 (OCH₃), 109.3 (CH), 120.2(CH), 125.8 (C_(quat)), 129.0 (CH), 134.3 (C_(quat)), 135.2 (CH), 148.5(C_(quat)), 164.0 (C_(quat)), 184.6 (C═O), 185.1 (C═O)

MS (EI):m/z (%): 202.1 ([M]⁺, 100), 174.0 (29), 203.1 ([M+H]⁺, 13):

elemental analysis calcd for C₁₂H₁₀O₃ (%) C, 71.28; H, 4.98. Found: C,71.16; H, 5.05.

4.2. 6-methyl-2-methylnaphthalene-1,4-dione

Yield: 68% yellow powder

¹H NMR (300 MHz, CDCl₃): δ=7.99 (d, J=7.9 Hz, 1H), 7.85 (s, 1H), 7.52(d, J=7.9 Hz, 1H), 6.81 (q, J=1.6 Hz, 1H), 2.49 (s, 3H), 2.19 (d, J=1.6Hz, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=185.4 (C═O), 185.2 (C═O), 148.2 (C_(quat)),144.7 (C_(quat)), 135.5 (CH), 135.0 (C_(quat)), 134.3 (CH), 132.2(C_(quat)), 126.7 (CH), 126.4 (CH), 21.8 (CH₃), 16.5 (CH₃) ppm

4.3. 7-methoxy-2-methylnaphthalene-1,4-dione

Yield: 52% yellow powder

¹H NMR (300 MHz, CDCl₃): δ=8.03 (d, J=2.7 Hz, 1H), 7.56 (d, J=2.7 Hz,1H), 7.21 (dd, J=8.6 Hz, J=2.7 Hz, 1H), 6.8 (q, J=1.6 Hz, 1H), 3.97 (s,3H), 2.2 (d, J=1.6 Hz, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=¹³C NMR (75 MHz, CDCl₃): δ=185.7 (C═O), 184.2(C═O), 163.9 (C_(quat)), 147.6 (C_(quat)), 135.9 (CH), 134.1 (C_(quat)),128.5 (CH), 125.8 (C_(quat)), 120.1 (CH), 109.9 (CH), 55.9 (OCH₃), 16.4(CH₃) ppm.

MS (EI):m/z (%): 202.1 ([M]⁺, 100)

elemental analysis calcd for C₁₂H₁₀O₃ (%) C, 71.28; H, 4.98. Found: C,71.35; H, 4.90.

4.4. 6-fluoro-2-methylnaphthalene-1,4-dione

Yield: 65%

¹H NMR (200 MHz, CDCl₃): δ=2.22 (d, J=1.4 Hz, 3H), 6.88 (d, J=1.4 Hz,1H), 7.72 (dd, 8.5 Hz, J=2.7 Hz, 1H), 7.40 (ddd, J=8.5 Hz, J_(H-F)=8.1Hz, J=2.7 Hz, 1H) 8.16 (dd, J=8.5 Hz, J_(H-F)=5.3 Hz, 1H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=184.2 (C═O), 183.7 (C═O), 166.3 (d,J_(C-F)=260.5 Hz, C_(q)), 148.5 (C_(q)), 135.6 (CH), 134.9 (d,J_(C-F)=8.0 Hz, C_(q)), 129.8 (d, J_(C-F)=8.7 Hz, CH), 125.6 (C_(q)),120.7 (d, J_(C-F)=22.2 Hz, CH), 112.8 (d, J_(C-F)=23.7 Hz, CH), 16.5(CH₃) ppm.

4.5. 6-chloro-2-methylnaphthalene-1,4-dione

Yield: 44% yellow powder

m.p. (hexane/ethyl acetate): 104-105° C.

¹H NMR (400 MHz, CDCl₃): δ=8.06 (d, J=8.6 Hz, 1H), 8.04 (d, J=2.2 Hz,1H), 7.68 (dd, J=8.6 Hz, J=2.2 Hz, 1H), 6.86 (q, J=1.5 Hz, 1H), 2.21 (d,J=1.5 Hz, 3H) ppm

¹³C NMR (100 MHz, CDCl₃) δ=16.5 (CH₃), 126.3 (CH), 128.4 (CH), 130.4(C_(quat)), 133.4 (C_(quat)), 133.7 (CH), 135.5 (CH), 140.7 (C_(quat)),148.6 (C_(quat)), 183.8 (C═O), 184.6 (C═O)

MS (EI):m/z (%): 206.0 ([M]⁺, 100), 207.1 ([M+H]⁺, 15), 191.0 ([M-CH₃]⁺,5)

elemental analysis calcd for C₁₁H₇O₂Cl (%) C, 63.40; H, 3.41. Found C,63.11; H, 3.49.

4.6. 6,7-dimethoxy-2-methylnaphthalene-1,4-dione

Yield: 60% orange powder

m.p. (hexane/ethyl acetate): 183° C. dec.

¹H NMR (300 MHz, CDCl₃): δ=2.17 (d, J=1.5 Hz, 3H), 4.02 (s, 3H), 4.04(s, 3H), 6.74 (q, J=1.5 Hz, 1H), 7.48 (s, 1H), 7.52 (s, 1H).

¹³C NMR (75 MHz, CDCl₃) δ=16.6, 56.7 (2×OCH₃) 107.8, 108.2, 127.2,127.3, 135.4, 147.9, 153.5, 153.6, 184.8, 185.2.

MS (EI):m/z (%): 232 ([M]⁺, 100), 217 (([M-CH₃]⁺, 8).

elemental analysis calcd for C₁₃H₁₂O₄ (%) C, 67.23; H, 5.21. Found: C,66.99; H, 4.90.

The spectroscopic and physical data were identical to those reported inthe literature (Bringmann G. and Al, 2011, 46, 5778-5789)

4.7. 7-fluoro-2-methylnaphthalene-1,4-dione

Yield: 65% yellow powder

m.p (hexane/ethyl acetate):109-110° C.

¹H NMR (300 MHz, CDCl₃): δ=8.1 (dd, J=8.3 Hz, J=5.3 Hz, 1H), 7.74 (dd,J=8.3 Hz, J=2.7 Hz, 1H), 7.21 (td, J=8.6 Hz, J=2.7 Hz, 1H), 6.8 (q,J=1.7 Hz, 1H), 3.97 (s, 3H), 2.20 (d, J=1.6 Hz, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.5 (C═O), 183.6 (C═O), 167.7 (C_(q)),164.3 (C_(q)), 148.3 (d, J_(C-F)=2.0 Hz, CH), 135.8 (CH), 134.7 (d,J_(C-F)=7.7 Hz, C_(q)), 129.3 (d, J_(C-F)=8.9 Hz, CH), 128.9 (d,J_(C-F)=3.3, C_(q)), 120.8 (d, J_(C-F)=22.1, CH), 113.3 (d,J_(C-F)=22.1, CH), 16.4 (CH₃) ppm.

MS (EI):m/z (%): (190.0 [M]⁺, 100), 191.0 ([M+H]⁺, 13)

elemental analysis calcd for C₁₁H₇O₂F (%) C, 69.47; H, 3.71. Found C,69.11; H, 3.49.

EXAMPLE 5 General Procedure for Alpha-Bromination of Propiophenone

It is based on the work from S. Uemura & S.-I. Fukuzawa J. Chem. Soc.,Perkin Trans. I, 1986, 1983-1987

To a stirred solution of propiophenone in acetic acid (1 eq, 2.45mmol·mL⁻¹) was added dropwise bromine/AcOH (1 eq, 20 mmol·mL⁻¹) keepingthe temperature below 20° C. The reaction mixture was stirred at R.T.for 1-2 h, during which period the orange/red color of the mixtureturned yellowish. The reaction mixture was poured in 10 volumes ofwater. The precipitated solids was filtered, washed with water and driedand directly used as such in the next step. (Note: sometimes the bromocompounds may not crystallize, the aqueous phase should then beextracted with an organic solvent such as dichloromethane).

5.1. 2-bromo-1-(4-fluorophenyl)propan-1-one

Yield: >98% (colorless oil, LACRYMATORY!!)

¹H NMR (200 MHz, CDCl₃): δ=1.90 (d, J=6.6 Hz, 3H), 5.25 (q, J=6.6 Hz,1H), 7.16 (mc, 2H), 8.06 (dd, J=8.7 Hz, J_(H-F)=5.4 Hz, 2H) ppm

Due to its lacrymatory nature the crude was directly engaged in the nextstep (6.1).

5.2. 2-bromo-1-p-tolylpropan-1-one

Yield: 99% white powder

¹H NMR (300 MHz, CDCl₃): δ=7.92 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz,2H), 5.28 (q, J=6.6 Hz, 1H), 2.42 (s, 3H), 1.89 (d, J=6.6 Hz, 3H) ppm.

5.3. 2-bromo-1-(4-chlorophenyl)propan-1-one

Yield: 99% white powder

¹H NMR (300 MHz, CDCl₃): δ=7.99 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz,2H), 5.24 (q, J=6.6 Hz, 1H), 1.92 (d, J=6.6 Hz, 3H) ppm.

Due to its lacrymatory nature the crude was directly engaged in the nextstep (6.3).

EXAMPLE 6 General Procedure for Nucleophilic Substitution ofα-Bromopropiophenone

It is based on the work from A. C. Vargas, B. Quiclet-Sire, S. Z. ZardOrg. Lett. 2003, 5, 3717-3719

To a solution of α-bromopropiophenone in acetone (1 eq, 0.51 mmol·mL⁻¹)at 0° C. was added Potassium O-ethyl xanthate (1.1 eq) and the reactionmixture was stirred until disappearance of the starting material.Acetone was then evaporated and the resulting mixture was partitionedbetween water and dichloromethane. The organic phase was dried withbrine and then MgSO₄. The crude was purified by flash chromatography onsilica gel (cyclohexane/EtOAc).

6.1. O-ethyl S-1-(4-fluorophenyl)-1-oxopropan-2-yl carbonodithioate

Yield: 57% (yellow oil)

This compound was mentioned twice in the literature (Liard et al.Tetrahedron Lett. 1997, 38, 1759-1762. Quiclet-Sire et al. Synlett 2003,75-78) but without any analytical data.

¹H NMR (300 MHz, CDCl₃): δ=1.37 (t, J=7.2 Hz, 3H), 1.61 (d, J=7.1 Hz,3H), 4.63 (q, J=7.2 Hz, 2H), 5.43 (q, J=7.1 Hz, 1H), 7.15 (mc, 2H), 8.05(dd, J=8.7 Hz, J_(H-F)=5.4 Hz, 2H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=13.7 (CH₃), 17.0 (CH₃), 49.9 (CH), 70.8(CH₂), 115.9 (d, J_(C-F)=21.7 Hz, 2×CH), 131.3 (d, J_(C-F)″=9.1 Hz,2×CH), 164.3 (C_(quat)), 167.7 (C_(quat)), 195.2 (C═O), 212.9 (C═S) ppm

6.2. O-ethyl S-1-oxo-1-p-tolylpropan-2-yl carbonodithioate

Yield: 90% brown oil

¹H NMR (300 MHz, CDCl₃): δ=7.92 (d, J=7.1 Hz, 2H), 7.28 (d, J=8.2 Hz,2H), 5.45 (q, J=7.1 Hz, 1H), 4.62 (q, J=7.2 Hz, 2H), 2.41 (s, 3H), 1.61(d, J=7.2, 3H), 1.36 (t, J=7.1 Hz, 3H) ppm

6.3. S-1-(4-chlorophenyl)-1-oxopropan-2-yl O-ethyl carbonodithioate

Yield: 75% brown oil

¹H NMR (300 MHz, CDCl₃): δ=7.88 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.25 Hz,2H), 5.34 (q, J=7.1 Hz, 1H), 4.52 (q, J=7.2 Hz, 2H), 1.53 (d, J=7.1,3H), 1.31 (t, J=7.2 Hz, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=13.7 (CH₃), 16.8 (CH₃), 49.9 (CH), 70.8(CH₂), 129.1 (2×CH), 130.3 (2×CH), 133.4 (C_(quat)), 140.1 (C_(quat)),195.6 (C═O), 212.8 (C═S) ppm.

EXAMPLE 7 General Procedure for Preparation ofα-methyl-γ-O-pivalate-tetralones

It is based on the work from A. C. Vargas et al. cited above.

A solution of xanthate (15 mmol, 1 eq), vinyl pivalate (30 mmol, 2 eq)in 15 mL of dichloroethane was saturated with a stream of Argon for10-15 min. The solution was refluxed under Argon. Laurolyl peroxide(DLP) was then added (5 mol %) to the refluxing solution followed byadditional portions (2-3 mol %, every 1 h-1 h30). When TLC monitoringshowed that starting material was consumed (after 6 to 8 additions ofDLP), the solution was cooled to room temperature and filtrated througha column of basic alumina (eluant: dicholoromethane). The organic phasewas evaporated. The crude was dissolved in dichloroethane (350 mL) andthe solution was saturated with a stream of Argon for 10-15 nm. If thearomatic moiety bears an electrowithdrawing substituent thencamphorsulfonic acid (CSA, 0.1 eq) is added. The solution was refluxedunder Argon. Laurolyl peroxide (DLP) was then added to the refluxingsolution followed by additional portions (20 mol %, every 1 h-1 h30).When TLC monitoring showed that starting material was consumed (after1.2-1.4 eq of DLP), the solution was cooled to room temperature andfiltrated through a column of basic alumina (eluant:dicholoromethane).The organic phase was evaporated. The crude was purified by flashchromatography (cyclohexane/EtOAc) on silica gel to obtain an oil whichcrystallized on standing.

7.1. cis- andtrans-7-fluoro-3-methyl-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl pivalate

Yield: 26% (yellow oil which crystallized upon standing) after flashchromatography (silica gel, solvents:petroleumether/EtOAc 200/10). Thetitle compounds were obtained as a mixture (1/1) of cis and transdiatereoisomers.

¹H NMR (300 MHz, CDCl₃): DIA1 δ=1.31 (s, 3H), 1.32 (s, 9H), 1.92 (mc,1H), 2.49 (dt, J=12.5 Hz, J=4.7 Hz, 1H), 2.72 (mc, 1H), 6.15 (dd, J=11.2Hz, J=4.7 Hz, 1H), 7.00 (ddd, J=9.5 Hz, J=2.7 Hz, J=0.9 Hz, 1H), 7.12(m, 1H), 8.10 (dd, J=8.8 Hz, J=5.9 Hz, 1H) ppm

¹H NMR (300 MHz, CDCl₃): DIA2 δ=1.19 (s, 9H), 1.28 (s, 3H), 2.17 (ddd,J=14.3 Hz, J=11.4 Hz, J=3.9 Hz, 1H), 2.35 (dt, J=14.3 Hz, J=4.6 Hz, 1H),3.00 (mc, 1H), 6.06 (t, J=3.9 Hz, 1H), 7.11 (m, 2H), 8.10 (dd, J=8.8 Hz,J=5.9 Hz, 1H) ppm

¹³C NMR (75 MHz, CDCl₃): DIA1 δ=15.3 (CH₃), 27.2 (3×CH₃, t-Bu), 37.3(CH₂), 39.0 (C_(quat), t-Bu), 40.6 (CH), 68.9 (OCH), 112.3 (d,J_(C-F)=22.8 Hz, CH), 115.7 (d, J_(C-F)=21.7 Hz, CH), 128.2 (d,J_(C-F)=2.2 Hz, C_(quat)), 130.7 (d, J_(C-F)=9.9 Hz, CH), 145.7 (d,J_(C-F)=8.9 Hz, C_(quat)), 166.0 (d, J_(C-F)=256 Hz, C_(quat)), 177.9(OC═O), 197.3 (C═O) ppm

¹³C NMR (75 MHz, CDCl₃): DIA2 δ=14.1 (CH₃), 27.0 (3×CH₃, t-Bu), 36.0(CH₂), 37.0 (CH), 67.6 (OCH), 115.8 (d, J_(C-F)″=21.9 Hz, CH), 116.7 (d,J_(C-F)=21.9 Hz, CH), 128.5 (d, J_(C-F)=2.3 Hz, C_(quat)), 130.5 (d,J_(C-F)=9.6 Hz, CH), 149.9 (d, J_(C-F)=9.0 Hz, C_(quat)), 165.7 (d,J_(C-F)=256 Hz, C_(quat)), 177.7 (OC═O), 198.2 (C═O) ppm

7.2. 3,7-dimethyl-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl pivalate

Yield: 28% brown oil

¹H NMR (300 MHz, CDCl₃): DIA1 δ=1.18 (s, 3H), 1.32 (s, 9H), 1.85-1.92(m, 1H), 2.41 (s, 3H) 2.47 (dt, J=12.4 Hz, J=4.7 Hz, 1H), 2.62-2.72 (m,1H), 6.17 (dd, J=10.9 Hz, J=4.9 Hz, 1H), 7.11 (s, 1H), 7.23 (d, J=8.6,1H) 8.10 (d, J=8.6, 1H), 1H)

¹H NMR (300 MHz, CDCl₃): DIA2 δ=1.19 (s, 9H), 1.28 (s, 3H), 2.17 (ddd,J=14.3 Hz, J=11.4 Hz, J=3.9 Hz, 1H), 2.35 (dt, J=14.3 Hz, J=4.6 Hz, 1H),2.41 (s, 3H), 3.00 (mc, 1H), 6.05 (t, J=3.6 Hz, 1H), 7.11 (s, 1H), 7.23(d, J=8.6, 1H) 8.10 (d, J=8.6, 1H), 1H).

7.3. cis- andtrans-7-chloro-3-methyl-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl pivalate

Yield: 25% brown oil

¹H NMR (300 MHz, CDCl₃): DIA1 δ=1.18 (s, 3H), 1.32 (s, 9H), 1.85-1.92(m, 1H), 2.47 (dt, J=12.4 Hz, J=4.7 Hz, 1H), 2.62-2.72 (m, 1H), 6.17(dd, J=10.9 Hz, J=4.9 Hz, 1H), 7.11 (s, 1H), 7.23 (d, J=8.6, 1H) 8.10(d, J=8.6, 1H), 1H) ppm.

¹H NMR (300 MHz, CDCl₃): DIA2 δ=1.19 (s, 9H), 1.28 (s, 3H), 2.17 (ddd,J=14.3 Hz, J=11.4 Hz, J=3.9 Hz, 1H), 2.35 (dt, J=14.3 Hz, J=4.6 Hz, 1H),3.00 (mc, 1H), 6.05 (t, J=3.6 Hz, 1H), 7.11 (s, 1H), 7.23 (d, J=8.6, 1H)8.10 (d, J=8.6, 1H), 1H) ppm.

¹³C NMR (75 MHz, CDCl₃): DIA1 δ=15.4 (CH₃), 27.2 (3×CH₃, t-Bu), 37.2(CH₂), 39.0 (C_(quat), t-Bu), 40.6 (CH), 69.2 (OCH), 113.4 (CH), 116.1(CH), 127.4 (C_(quat)), 131.4 (CH), 145.2 (C_(quat)), 166.2 (C_(quat)),178.0 (OC═O), 198.5 (C═O) ppm

¹³C NMR (75 MHz, CDCl₃): DIA2 δ=15.3 (CH₃), 27.0 (3×CH₃, t-Bu), 36.2(CH₂), 37.5 (CH), 38.9 (C_(quat), t-Bu), 68.2 (OCH), 115.8 (CH), 116.7(d, J_(C-F)=21.9 Hz, CH), 128.5 (C_(quat)), 130.5 (CH), 149.9(C_(quat)), 165.7 (C_(quat)), 177.9 (OC═O), 199.5 (C═O) ppm.

EXAMPLE 8 General Procedure for 2-methylnaphtol Preparation byDehydration

It is based on the work from A. C. Vargas et al. (cited above).

A solution of tetralone (2.5 mmol, 1.0 eq) in toluene (75 mL) andp-TsOH—H₂O (7.2 mmol, 2.9 eq) was refluxed was 3-4 h with a Dean-starkapparatus. When starting material was totally consumed, the reactionmixture was allowed to cool to room temperature, neutralized withsaturated Na₂CO₃, extracted with CH₂Cl₂, dried (MgSO₄) and evaporatedunder reduced pressure. The naphtol was directly used as such in thenext step.

8.1. 6-fluoro-2-methylnaphthalen-1-ol

Yield: >98%

¹H NMR (300 MHz, CD₂Cl₂): δ=2.07 (s, 3H), 6.91 (td, J=2.6 Hz, J=9.0 Hz,1H), 6.98 (AB system, J=8.6 Hz, Δν=12.3 Hz, 2H), 7.07 (dd, J=2.6 Hz,J_(H-F)=10.1 Hz, 1H), 7.85 (dd, 5.3 Hz, J=9.3 Hz, 1H) ppm

¹³C NMR (75 MHz, CD₂Cl₂): δ=16.0 (CH₃), 111.1 (d, J_(C-F)=20.0 Hz, CH),115.9 (d, J_(C-F)=25.2 Hz, CH), 116.4 (C_(q)), 120.1 (d, J_(C-F)=5.2 Hz,CH), 122.2 (C_(q)), 124.7 (d, J_(C-F)=9.2 Hz, CH), 131.2 (CH), 135.0 (d,J_(C-F)=9.2 Hz, C_(q)), 149.7 (C_(q)), 161.3 (d, J_(C-F)=246.0 Hz,C_(q)) ppm

MS (EI): m/z (%): 176.0 ([M]⁺, 100), 177.1 ([M+H]⁺, 13), 147.0 (36),175.0 ([M−H]⁺, 33).

8.2. 2,6-dimethylnaphthalen-1-ol

Yield: 90% Brown powder

¹H NMR (300 MHz, CDCl₃): δ=8.01 (d, J=8.6 Hz, 1H), 7.54 (s, 1H),7.32-7.18 (m, 4H), 2.49 (s, 3H), 2.39 (s, 3H) ppm.

8.3. 7-chloro-2-dimethylnaphthalen-1-ol

Yield: 90% Brown powder

¹H NMR (300 MHz, CDCl₃): δ=8.01 (d, J=8.6 Hz, 1H), 7.54 (s, 1H),7.32-7.18 (m, 4H), 2.39 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=15.6 (CH₃), 116.4 (C_(q)) 119.2 (CH), 122.6(C_(q)), 123.1 (CH), 126.1 (CH), 126.2 (CH), 130.3 (CH), 131.3 (C_(q)),134.3 (C_(q)), 148.4 (C_(q)) ppm.

EXAMPLE 9 General Procedure for Preparation of Menadiones Ia1 byDiels-Alder Reaction

A solution of bromomethylquinone (1.0 eq) in dry CH₂Cl₂ (0.15 mmol/ml)was added to a suspension of ZnBr₂ (1.2 eq) in dry CH₂Cl₂ (1.5 mmol/ml).The mixture was stirred for 5 minutes and the appropriated diene wasadded (10 eq). After stirring overnight the reaction mixture wasquenched with a solution of saturated NH₄Cl. The reaction mixture wasextracted with CH₂Cl₂, and the combined CH₂Cl₂ layers were washed withbrine and dried with MgSO₄. Pyridine (2 eq) was added and the mixturewas stirred at rt for 4 h. CH₂Cl₂ was evaporated to yield thehydroquinone as yellow oil. The hydroquinone (1 eq) was solubilized indioxane (0.3M) and to this solution was added2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.0 eq) at roomtemperature. After completion of the reaction (TLC monitoring), thewhite precipitate was removed by filtration. The filtrate wasconcentrated under reduced pressure.

The crude was purified by column chromatography (silica gel, eluantcyclohexane/EtOAc, 4:1).

9.1. 2,5-dimethylnaphthalene-1,4-dione

Yield: 50% (yellow needles)

Mp (from hexane/ethyl acetate): 93° C.

¹H NMR (300 MHz, CDCl₃): δ=8.04 (dd, J=7.5 Hz, 1.6 Hz, 1H), 7.61-7.50(m, 2H), 6.78 (q, J=1.6, 1H), 2.75 (s, 3H), 2.17 (d, J=1.6, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=187.1 (C═O), 186.0 (C═O), 146.2 (C_(q)),141.0 (C_(q)), 137.6 (CH), 137.4 (CH), 133.6 (C_(q)), 132.6 (CH), 129.7(C_(q)), 125.4 (CH), 22.6 (CH₃), 15.9 (CH₃) ppm.

MS (EI): m/z (%): 186.0 ([M]⁺, 100), 171 [M-CH₃]⁺, 12.3)

elemental analysis calcd (%) C₁₂H₁₀O₂: C, 77.40; H, 5.41. Found C,77.03; H, 5.63.

9.2. 2,6-dimethylnaphthalene-1,4-dione

Yield: 70% yellow powder

m.p (from hexane/ethyl acetate): 114-115° C. ¹H NMR (300 MHz, CDCl₃):δ=7.99 (d, J=7.9 Hz, 1H), 7.85 (s, 1H), 7.52 (d, J=7.9 Hz, 1H), 6.81 (q,J=1.6 Hz, 1H), 2.49 (s, 3H), 2.19 (d, J=1.6 Hz, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=185.4 (C═O), 185.2 (C═O), 148.2 (C_(quat)),144.7 (C_(quat)), 135.5 (CH), 135.0 (C_(quat)), 134.3 (CH), 132.2(C_(quat)), 126.7 (CH), 126.4 (CH), 21.8 (CH₃), 16.5 (CH₃) ppm.

MS (EI): m/z (%): 186.0 ([M]⁺, 100), 171 [M-CH₃]⁺, 10)

elemental analysis calcd (%) for C₁₂H₁₀O₂: C, 77.40; H, 5.41. Found C,77.12; H, 5.59.

9.3. 2,7-dimethylnaphthalene-1,4-dione

Yield: 57% Yellow needles;

m.p. (from hexane/ethyl acetate): 111-112° C.;

¹H NMR (300 MHz, CDCl₃): δ=7.95 (d, 2H, J=7.5 Hz, 1H),), 7.93 (s, 1H),7.50 (d, J=7.5 Hz, 1H), 6.81 (q, J=1.5 Hz, 1H), 2.49 (s, 3H), 2.19 (d,J=1.6 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃): d=184.5 (C═O), 184.1 (C═O), 148.2 (C_(q)),144.6 (C_(q)), 135.7 (CH), 134.3 (CH), 132.0 (C_(q)), 131.1 (C_(q)),126.8 (CH), 126.2 (CH), 21.8 (CH₃), 16.4 (CH₃) ppm.

MS (EI): m/z (%): 186.0 ([M]⁺, 100), 171 [M-CH₃]⁺, 15.3)

elemental analysis calcd (%) for C₁₂H₁₀O₂: C, 77.40; H, 5.41. Found C,77.77; H, 5.16.

The spectroscopic and physical data were identical to those reported inthe literature: Exact Saxena and Al. J. Nat. Prod. 1996, 59, 62-65.

9.4. 2,8-dimethylnaphthalene-1,4-dione

Yield: 70% (yellow needles)

m.p. (hexane/ethyl acetate): 132° C.

¹H NMR (300 MHz, CDCl₃): δ=8.00 (dd, J=7.3 Hz, 1.8 Hz, 1H), 7.62-7.49(m, 2H), 6.81 (q, J=1.19, 1H), 2.76 (s, 3H), 2.19 (d, J=1.19, 3H)

¹³C NMR (75 MHz, CDCl₃) 187.5 (C═O), 185.3 (C═O), 149.4 (C_(q)), 141.3(C_(q)), 137.6 (CH), 134.3 (CH), 133.7 (C_(q)), 132.8 (CH), 129.8(C_(q)), 125.0 (CH), 22.9 (CH₃), 16.8 (CH₃)

MS (EI): m/z (%): (186.0 [M]⁺, 100), 171 [M-CH₃]⁺, 17)

elemental analysis calcd (%) for C₁₂H₁₀O₂: C, 77.40; H, 5.41. Found C,77.74; H, 5.10.

9.5. 2,6,7-trimethylnaphthalene-1,4-dione

Yield: 40% (yellow needles)

Mp (from hexane/ethyl acetate): 111-112° C.

¹H NMR (300 MHz, CDCl₃): δ=7.77 (s, 1H), 7.70 (s, 1H), 6.68 (q, J=1.6Hz, 1H), 2.31 (s, 6H), 2.09 (d, J=1.6 Hz, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=185.7 (C═O), 185.3 (C═O), 147.8 (C_(q)),143.4 (C_(q)), 143.3 (C_(q)), 135.5 (CH), 130.3 (C_(q)), 130.2 (C_(q)),127.5 (CH), 127.1 (CH), 20.1 (2×CH₃), 16.4 (CH₃) ppm.

MS (EI): m/z (%): (200.0 [M]⁺, 100), 185 ([M-CH₃]⁺, 19)

Elemental analysis calcd (%) for C₁₃H₁₂O₂: C, 77.98; H, 6.04. Found C,77.68; H, 6.42.

EXAMPLE 10 General Procedure for Diels-Alder Reaction with Danishefsky'sDiene

1-Methoxy-3-(trimethylsiloxy)-1,3-butadiene (2.0 eq) was added dropwiseto a methylbromoquinone (1.0 eq) in CH₂Cl₂ (0.2M). The solution wasstirred at room temperature for 2 h, then pyridine (1.5 eq) and Silica(ca. 1.5 g/mmol) were added and the suspension stirred under air at rtfor 6 h. Concentration and flash column chromatography eluting withethyl acetate/toluene (1:2) gave thehydroxy-2-methylnaphthalene-1,4-dione.

10.1 6-hydroxy-2-methylnaphthalene-1,4-dione

Yield: 70% (Orange solid).

m.p. 175° C. (from hexane/ethyl acetate).

¹H NMR (300 MHz, CD₃OCD₃): δ 7.95 (d, J=8.4 Hz, 1H), 7.39 (d, J=2.5 Hz,1H), 7.22 (dd, J=8.4, 2.5 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 2.13 (d,J=1.6 Hz, 3H) ppm.

¹³C NMR (75 MHz, CD₃OCD₃) δ=185.5 (C═O), 184.5 (C═O), 163.4 (C_(q)),149.4 (C_(q)), 135.9 (CH), 135.6 (C_(q)), 130.0 (CH), 125.9 (C_(q)),121.3 (CH), 112.3 (CH), 16.4 (CH₃) ppm.

MS (EI) m/z (%): 188 ([M]⁺, 100), 160 (23).

elemental analysis calcd (%) for C₁₁H₈O₃: C, 70.21; H, 4.29. Found C,69.99; H, 4.32.

The spectroscopic and physical data were identical to those reported inthe literature (Bringmann G. and Al, 2011, 46, 5778-5789)

10.2 7-hydroxy-2-methylnaphthalene-1,4-dione

Yield: 86% (orange solid).

Mp (from hexane/ethyl acetate): 180° C. dec.

¹H NMR (300 MHz, CDCl₃): δ=10.86 (s, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.29(d, J=2.5 Hz, 1H), 7.13 (dd, J=7.9 Hz, 2.5 Hz, 1H), 6.83 (q, J=1.6 Hz,1H), 2.06 (d, J=1.6 Hz, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=185.2 (C═O), 183.4 (C═O), 162.5 (C_(q)),147.2 (C_(q)), 135.4 (CH), 133.8 (C_(q)), 128.4 (CH), 123.9 (C_(q)),120.5 (CH), 111.8 (CH), 15.7 (CH₃) ppm

MS (EI) m/z (%): 188.0 ([M]⁺, 100), 160, (32)

elemental analysis calcd (%) for C₁₁H₈O₃: C, 70.21; H, 4.29. Found C,70.03; H, 4.06.

EXAMPLE 11 General Procedure for the Synthesis of Triflates Menadiones

To a solution of hydroxymenadione (1.0 eq) in CH₂Cl₂ (0.03M) was addedpyridine (2.0 eq) at room temperature under an argon atmosphere. After10 min, Tf₂O (1.5 eq.) was added at 0° C. and the mixture was warmed toroom temperature and stirred for 2 h. The reaction mixture was treatedwith a solution of 5% NaHCO₃ (1 ml/mmol). The mixture extracted withCH₂Cl₂. The organic phases were dried with MgSO₄ and concentrated invacuo to yield menadione triflate.

Note: usually the product does not need to be further purified and canbe directly engaged in the next step, the Kochi-Anderson reaction.

11.1 6-methyl-5,8-dioxo-5,8-dihydronaphthalen-2-yltrifluoromethanesulfonate

Yield: 100% (yellow solid).

Mp (petroleumether/ethyl acetate) 82° C.

¹H NMR (CDCl₃): δ=8.25 (d, J=8.4 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.61(dd, J=8.4, 2.5 Hz, 1H), 6.93 (q, J=1.6 Hz, 1H), 2.22 (d, J=1.6 Hz, 3H)

¹³C NMR (CDCl₃) δ=184.0 (C═O), 183.0 (C═O), 153.1 (C_(q)), 149.0(C_(q)), 136.0 (CH), 134.6 (C_(q)), 131.8 (CH), 129.7 (C_(q)), 126.5(CH), 118.8 (q, J_(C-F)=320.9 Hz, CF₃), 117.3 (CH), 16.7 (CH₃) ppm

MS (EI) m/z (%): 320 (100), 188 (35).

elemental analysis calcd (%) for C₁₂H₇F₃O₅S: C, 65.90; H, 3.78. Found C,65.58; H, 3.86.

The spectroscopic and physical data were identical to those reported inthe literature (Bringmann G. and Al, 2011, 46, 5778-5789)

11.2 7-methyl-5,8-dioxo-5,8-dihydronaphthalen-2-yltrifluoromethanesulfonate

Yield: 100% (yellow solid).

Mp (from hexane/ethyl acetate): 90-91° C.

¹H NMR (CDCl₃): δ=8.20 (d, J=8.6 Hz, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.63(dd, J=8.6 Hz, 2.5 Hz, 1H), 6.91 (q, J=1.6 Hz, 1H), 2.24 (d, J=1.6 Hz,3H) ppm.

¹³C NMR (CDCl₃) δ d=183.6 (C═O), 183.1 (C═O), 152.8 (C_(q)), 148.7(C_(q)), 135.8 (CH), 134.3 (C_(q)), 131.6 (CH), 129.1 (C_(q)), 126.4(CH), 119.3 (CH), 118.7 (q, J=319.9 Hz, CF₃), 16.4 (CH₃) ppm.

MS (EI) m/z (%): 320.09 ([M]⁺, 100), 321.09 ([M+H]⁺, 25).

elemental analysis calcd (%) for C₁₂H₇F₃O₅S: C, 65.90; H, 3.78. Found C,65.94; H, 3.64.

EXAMPLE 12 General Procedure for the Synthesis of Compounds Ia1

The corresponding menadione derivatives, compounds of formula (IIa1), (1eq, 0.05 mmol·mL⁻¹) and a phenyl acetic acid derivative (compounds offormula (III)) (2 eq) were added to a stirred solution of MeCN/H₂O (3/1)and heated at 85° C. (70° C. in the flask). AgNO₃ (0.35 eq) was addedfirst and then (NH₄)₂S₂O₈ (1.3 eq, 0.36 mmol·mL⁻¹) in MeCN/H₂O (3/1) wasadded dropwise. The reaction mixture was then heated 2-3 hours at 85° C.MeCN was evaporated and the mixture was extracted with DCM. The crudemixture was purified by flash chromatography on silica gel using amixture diethyl ether and cyclohexane. When necessary, the compound wasrecristallised from hexane or a mixture of EtOAc/hexane.

12.1 3-(4-bromobenzyl)-6-methoxy-2-methylnaphthalene-1,4-dione

Yield: 78% (yellow needles)

m.p. (from hexane/EtOAc): 135-137° C.

¹H NMR (300 MHz, CDCl₃): δ=8.04 (d, J=8.6 Hz, 1H), 7.51 (d, J=2.6 Hz,1H), 7.25 ((AB)₂ system, J=8.0 Hz, Δν=40.9 Hz, 4H), 7.17 (dd, J=8.6 Hz,J=2.6 Hz, 1H), 3.96 (s, 2H), 3.93 (s, 3H), 2.23 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=184.6 (C═O); 184.2 (C═O); 163.9 (Cq); 144.7(Cq); 144.2 (Cq); 137.1 (Cq); 133.9 (Cq); 131.6 (2×CH); 130.2 (2×CH);128.8 (CH), 125.6 (Cq); 120.3 (CH); 120.2 (Cq); 109.6 (CH); 55.8 (CH₃);31.9 (CH₂); 13.3 (CH₃) ppm

MS (EI): m/z (%): 370.0 ([M⁺], 27), 355.0 ([M-CH₃]⁺, 100)

elemental analysis calcd (%) for C₁₉H₁₅BrO₃: C, 61.47; H, 4.07; Br,21.52. Found C, 61.32; H, 4.14; Br, 21.30.

12.26-methoxy-2-methyl-3-(4-trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 80% (yellow needles)

m.p. (from hexane/EtOAc): 86-87° C.

¹H NMR (300 MHz, CDCl₃): δ=8.05 (d, J=8.7 Hz, 1H), 7.51 (d, J=2.8 Hz,1H), 7.44 ((AB)₂ system, J=7.8 Hz, Δν=53.6 Hz, 4H), 7.18 (dd, J=8.7 Hz,J=2.8 Hz, 1H), 4.07 (s, 2H), 3.94 (s, 3H), 2.24 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=184.6 (C═O); 184.1 (C═O); 163.9 (C_(q));145.0 (C_(q)); 143.9 (C_(q)); 142.3 (C_(q)); 133.9 (C_(q)); 128.9 (CH);128.8 (CH); 125.7 (C_(q)); 125.6 (q, J=3.7 Hz, 2×CH); 120.4 (CH); 109.7(CH); 55.9 (CH₃); 32.4 (CH₂); 13.3 (CH₃) ppm

MS (EI): m/z (%): 360.0 ([M⁺], 27), 345.0 ([M-CH₃]⁺, 100) elementalanalysis calcd (%) for C₂₀H₁₅F₃O₃: C, 66.67; H, 4.20. Found C, 66.64; H,4.58.

12.3. 3-(2,5-dimethoxybenzyl)-6-methoxy-2-methylnaphthalene-1,4-dione

Yield: 65% (orange needles)

m.p. (hexane/EtOAc): 109-110° C.

¹H NMR (300 MHz, CDCl₃): δ=8.04 (d, J=8.0 Hz, 1H), 7.53 (d, J=2.7 Hz,1H), 7.17 (dd, J=8.0 Hz, J=2.7 Hz, 1H), 6.81-6.63 (m, 3H), 3.99 (s, 2H),3.94 (s, 3H), 3.82 (s, 3H), 3.71 (s, 3H), 2.23 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.6 (C═O); 184.4 (C═O); 163.8 (C_(q));153.5 (C_(q)); 151.55 (C_(q)) 145.2 (C_(q)); 145.0.2 (C_(q)); 134.2(C_(q)); 128.7 (CH); 127.7 (C_(q)); 125.9 (C_(q)); 120.1 (CH), 116.2(CH); 110.9 (CH); 109.6 (CH); 56.0 (CH₃); 55.8 (CH₃); 55.6 (CH₃); 26.7(CH₂); 13.3 (CH₃) ppm.

MS (EI): m/z (%): 352.1 ([M⁺], 100), 337.2 ([M⁺-CH₃], 93) elementalanalysis calcd (%) for C₂₁H₂₀O₅: C, 71.58; H, 5.72. Found C, 71.23; H,5.98.

12.4.: 3-(3,5-dimethoxybenzyl)-6-methoxy-2-methylnaphthalene-1,4-dione

Yield: 71% (yellow needles)

m.p. (hexane/EtOAc): 149° C.

¹H NMR (300 MHz, CDCl₃): δ=8.03 (d, J=8.6 Hz, 1H), 7.52 (d, J=2.7 Hz,1H), 7.16 (dd, J=8.6 Hz, J=2.7 Hz, 1H), 6.38 (d, J=2.3 Hz, 2H), 6.30 (t,J=2.3 Hz, 1H), 3.96 (s, 2H), 3.93 (s, 3H), 3.75 (s, 6H), 2.23 (s, 3H)ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.6 (C═O); 184.3 (C═O); 163.8 (C_(q));160.9 (C_(q)); 144.8 (C_(q)) 144.5 (C_(q)); 140.2 (C_(q)); 134.1(C_(q)); 128.8 (CH); 125.8 (C_(q)); 120.1 (CH), 109.7 (CH); 106.8(2×CH); 98.0 (CH); 55.8 (CH₃); 55.3 (CH₃); 32.5 (CH₂); 13.3 (CH₃) ppm.

MS (EI): m/z (%): 352.1 ([M⁺], 100), 337.2 ([M⁺-CH₃], 93)

elemental analysis calcd (%) for C₂₁H₂₀O₅: C, 71.58; H, 5.72. Found C,71.44; H, 5.79.

12.5. 3-(4-bromobenzyl)-6-fluoro-2-methylnaphthalene-1,4-dione

Yield: 85% (yellow needles)

m.p. (from hexane/EtOAc) 127-129° C.

¹H NMR (300 MHz, CDCl₃): δ=8.15 (dd, J=8.6 Hz, 5.3 Hz, 1H), 7.74 (dd,J=8.6 Hz, 2.7 Hz, 1H), 7.44 ((AB)₂ system, J=7.6 Hz, Δν=27.6 Hz, 4H),7.40 (m, 1H), 3.98 (s, 21H), 2.26 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=183.9 (C═O); 183.5 (C═O); 166.0 (d, J=265.0Hz, C_(q)); 144.9 (C_(q)); 144.8 (C_(q)); 136.8 (C_(q)); 134.5 (d, J=8.0Hz, C_(q)); 131.8 (2×CH); 130.3 (2×CH); 129.7 (d, J=8.9 Hz, CH); 128.7(C_(q)); 120.8 (d, J=23.0 Hz, CH); 120.4 (C_(q)); 113.2 (d, J=23.2 Hz,CH); 31.9 (CH₂); 13.3 (CH₃) ppm

MS (EI): m/z (%): 358.0 ([M⁺], 17), 343.0 ([M-CH₃]⁺, 100) elementalanalysis calcd (%) for C₁₈H₁₂BrFO₂: C, 60.19; H, 3.37; Br, 22.25. FoundC, 60.08; H, 3.58; Br, 22.36.

12.6.6-fluoro-2-methyl-3-(4-trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 41% (yellow needles)

m.p. (from hexane) 106-107° C.

¹H NMR (300 MHz, CDCl₃): δ=8.15 (dd, J=8.6 Hz, 5.3 Hz, 1H), 7.74 (dd,J=8.6 Hz, 2.7 Hz, 1H), 7.44 ((AB)₂ system, J=7.8 Hz, Δν=58.8 Hz, 4H),7.40 (dd, J=8.6 Hz, 2.7 Hz, 1H), 4.09 (s, 2H), 2.26 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=183.8 (C═O); 183.4 (C═O); 166.0 (d, J=256.0Hz, C_(q)); 145.1 (C_(q)); 144.5 (C_(q)); 141.9 (C_(q)); 134.4 (d, J=7.8Hz, C_(q)); 129.7 (d, J=8.8 Hz, CH); 129.1 (C_(q)); 128.8 (2×CH); 125.9(C_(q)); 125.6 (q, 3.3 Hz, 2×CH); 120.8 (d, J=22.7 Hz, CH); 113.2 (d,J=23.4 Hz, CH); 32.4 (CH₂); 13.4 (CH₃) ppm

MS (EI): m/z (%): 349.0 [M+H⁺], 5), 333.0 ([M-CH₃]⁺, 100)

elemental analysis calcd (%) for C₁₉H₁₂F₄O₂: C, 65.52; H, 3.47. Found C,65.39; H, 3.58.

12.7. 3-(4-bromobenzyl)-7-methoxy-2-methylnaphthalene-1,4-dione

Yield: 63% (yellow needles)

m.p. (from hexane/EtOAc) 149-151° C.

¹H NMR (300 MHz, CDCl₃): δ=8.05 (d, J=8.9 Hz, 1H), 7.55 (d, J=2.7 Hz,1H), 7.40, (d, J=8.3 Hz, 2H), 7.19 (dd, J=8.7 Hz, 2.7 Hz, 1H), 7.12 (d,J=8.2 Hz, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 2.23 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=185.3 (C═O); 183.6 (C═O); 163.9 (C_(q));144.8 (C_(q)); 144.0 (C_(q)); 137.2 (C_(q)); 134.1 (d, J=8.0 Hz, C_(q));131.7 (2×CH); 130.3 (2×CH); 129.0 (CH); 125.5 (C_(q)); 120.2 (d, J=31.1Hz, CH); 120.2 (C_(q)); 109.3 (d, J=Hz, CH), 56.1 (CH₃); 31.9 (CH₂);13.3 (CH₃) ppm

MS (EI): m/z (%): 357.1 ([M⁺-CH₃], 65), 372.1 ([M⁺], 23), 355 (100),276.1 ([M⁺-CH₃—Br], 46)

elemental analysis calcd (%) for elemental analysis calcd (%) forC₁₉H₁₅BrO₃: C, 61.47; H, 4.07; Br, 21.52. Found C, 61.18; H, 4.13.

12.8.7-methoxy-2-methyl-3-(4-trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 70% (yellow needles)

m.p. (from hexane/EtOAc) 137-139° C.

¹H NMR (300 MHz, CDCl₃): δ=8.03 (d, J=8.6 Hz, 1H), 7.53 (d, J=2.5 Hz,2H), 7.51, (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 7.18 (dd, J=8.6 Hz, 2.5 Hz,1H), 3.98 (s, 3H), 3.96 (s, 3H), 2.23 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=185.2 (C═O), 183.5 (C═O), 164.0 (C_(q)),144.5 (C_(q)), 144.3 (C_(q)), 142.3 (C_(q)), 134.0 (C_(q)) 128.7 (q,J=31 Hz, C_(q)), 125.4 (C_(q)), 124.1 (q, J=270 Hz, CF₃), 123.5 (q,J=3.4 Hz 2×CH), 122.3 (C_(q)), 120.2 (CH), 109.6 (CH), 55.9 (CH₃), 32.3(CH₂), 13.3 (CH₃) ppm

MS (EI): m/z (%): 360.1 ([M⁺], 39), 345.0 ([M⁺-CH₃], 100), 343.1 (50)elemental analysis calcd (%) for C₂₀H₁₅F₃O₃: C, 66.67; H, 4.2. Found C,66.64; H, 4.58.

12.9. 3-(3,5-dimethoxybenzyl)-7-methoxy-2-methylnaphthalene-1,4-dione

Yield: 77% (orange needles)

m.p. (from hexane/EtOAc): 151-153° C.

¹H NMR (300 MHz, CDCl₃): δ=7.95 (d, J=8.6 Hz, 1H), 7.44 (d, J=2.7 Hz,1H), 7.08 (dd, J=8.6 Hz, J=2.7 Hz, 1H), 6.30 (d, J=2.2 Hz, 2H), 6.22 (t,J=2.2 Hz, 1H), 3.88 (s, 2H), 3.86 (s, 3H), 3.67 (s, 6H), 2.14 (s, 3H)ppm.

¹³C NMR (75 MHz, CDCl₃): δ=185.4 (C═O); 183.7 (C═O); 163.8 (C_(q));160.9 (C_(q)); 144.8 (C_(q)) 144.5 (C_(q)); 140.2 (C_(q)); 134.1(C_(q)); 128.8 (CH); 125.8 (C_(q)); 120.1 (CH), 109.7 (CH); 106.8(2×CH); 98.0 (CH); 55.8 (—OCH₃); 55.3 (—OCH₃×2); 32.5 (CH₂); 13.3 (CH₃)ppm.

MS (EI): m/z (%): 352.1 ([M⁺], 86), 337.2 ([M⁺-CH₃], 100)

elemental analysis calcd (%) for C₂₁H₂₀O₅: C, 71.58; H, 5.72. Found C,71.41; H, 5.82.

12.10. 3-(2,5-dimethoxybenzyl)-6-methoxy-2-methylnaphthalene-1,4-dione

Yield: 65% (orange needles)

m.p. (from hexane/EtOAc): 180° C. dec.

¹H NMR (300 MHz, CDCl₃): δ=8.05 (d, J=8.6 Hz, 1H), 7.55 (d, J=2.7 Hz,1H), 7.18 (dd, J=8.6 Hz, J=2.7 Hz, 1H), 6.81-6.62 (m, 3H), 4.00 (s, 2H),3.96 (s, 3H), 3.82 (s, 3H), 3.71 (s, 3H), 2.16 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=185.5 (C═O); 183.7 (C═O); 163.7 (C_(q));153.5 (C_(q)); 151.55 (C_(q)) 145.5 (C_(q)); 144.0 (C_(q)); 134.2(C_(q)); 128.9 (CH); 127.8 (C_(q)); 125.8 (C_(q)); 120.0 (CH), 116.2(CH); 110.9 (CH); 109.4 (CH); 56.0 (CH₃); 55.9 (CH₃); 55.6 (CH₃); 26.6(CH₂); 13.0 (CH₃) ppm.

MS (EI): m/z (%): 352.1 ([M⁺], 44), 337.2 ([M⁺-CH₃], 53)

elemental analysis calcd (%) for C₂₁H₂₀O₅: C, 71.58; H, 5.72. Found C,71.47; H, 5.76.

12.11.6,7-dimethoxy-2-methyl-3-(4-(trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 80% (orange powder)

m.p. (from hexane/EtOAc): >200° C. dec

¹H NMR (300 MHz, CDCl₃): δ=7.50 (s, 1H), 7.49 (s, 1H), 7.44 ((AB)₂system, J=7.9 Hz, Δν=52.2 Hz, 4H), 4.05 (s, 2H), 4.01 (s, 3H), 4.00 (s,3H), 2.22 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.5 (C═O); 184.0 (C═O); 153.4 (C_(q));153.3 (C_(q)); 144.2 (C_(q)); 143.8 (C_(q)); 142.5 (C_(q)); 128.9(2×CH); 128.8 (q, J=32.8 Hz, C_(q)); 126.8 (C_(q)); 126.6 (C_(q)); 125.5(q, J=3.8 Hz, 2×CH); 124.1 (q, J=278.3 Hz, CF₃); 107.9 (CH); 107.8 (CH);56.5 (OMe); 56.4 (OMe); 32.3 (CH₂); 13.2 (CH₃) ppm.

MS (EI): m/z (%) 390.0 ([M⁺], 38), 375.10 ([M-CH₃]⁺, 100)

elemental analysis calcd (%) C₂₁H₁₇F₃O₄: C, 64.61; H, 4.39. Found C,64.44; H, 4.49.

12.12. 6,7-dimethoxy-2-methyl-3-(4-bromobenzyl)naphthalene-1,4-dione

Yield: 75% (orange powder)

m.p. (from hexane/EtOAc): >200° C. dec ¹H NMR (300 MHz, CDCl₃): δ=7.51(s, 1H), 7.50 (s, 1H), 7.25 ((AB)₂ system, J=8.6 Hz, Δν=81.2 Hz, 4H),4.01 (s, 3H), 4.00 (s, 3H), 3.95 (s, 2H), 2.21 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.7 (C═O); 184.1 (C═O); 153.3 (C_(q));153.2 (C_(q)); 144.1 (C_(q)); 143.9 (C_(q)); 137.3 (C_(q)); 131.7(2×CH); 130.3 (2×CH); 126.8 (C_(q)); 126.7 (C_(q)), 120.2 (C_(q)); 107.9(CH); 107.8 (CH); 56.5 (OCH₃), 56.4 (OCH₃), 31.9 (CH₂); 13.2 (CH₃) ppm.

MS (EI): m/z (%): (400.0 [M]⁺, 28), 385.0 ([M-CH₃]⁺, 100)

elemental analysis calcd (%) for C₂₀H₁₇BrO₄: C, 59.87; H, 4.27. Found C,59.62; H, 4.49.

12.13.2-(3,5-dimethoxybenzyl)-6,7-dimethoxy-3-methylnaphthalene-1,4-dione

Yield: 55% (orange powder)

m.p. (from hexane/EtOAc): 168-169° C.

¹H NMR (300 MHz, CDCl₃): 7.50 (s, 2H), 6.38 (d, J=2.3 Hz, 2H), 6.30 (t,J=2.3 Hz, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.94 (s, 2H), 3.75 (s, 6H),2.21 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.8 (C═O); 184.1 (C═O); 160.9 (C_(q));153.2 (C_(q)); 144.3 (C_(q)) 144.0 (C_(q)); 140.5 (C_(q)); 126.9(C_(q)); 126.8 (C_(q)); 108.0 (CH); 107.5 (CH), 106.8 (2×CH); 94.4 (CH);56.5 (CH₃); 56.4 (CH₃); 55.3 (2×CH₃); 32.5 (CH₂); 13.2 (CH₃) ppm.

MS (EI): m/z (%): (400.0 [M]⁺, 42), 385.0 ([M-CH₃]⁺, 100)

elemental analysis calcd (%) for C₂₂H₂₂O₆: C, 69.10; H, 5.80. Found C,68.84; H, 5.74.

12.14.2-14(2,5-dimethoxybenzyl)-6,7-dimethoxy-3-methylnaphthalene-1,4-dione

Yield: 72% (orange powder)

m.p. (from hexane/EtOAc): 166-167° C.

¹H NMR (300 MHz, CDCl₃): δ=7.52 (s, 1H), 7.51 (s, 1H), 6.80-6.62 (m,3H), 4.02 (s, 3H), 4.00 (s, 3H), 3.96 (s, 2H), 3.81 (s, 3H), 3.70 (s,3H), 2.14 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.9 (C═O); 184.0 (C═O); 153.5 (C_(q));153.2 (C_(q)); 153.1 (C_(q)); 151.5 (C_(q)) 144.7 (C_(q)); 144.4(C_(q)); 127.9 (C_(q)); 127.0 (C_(q)); 126.9 (C_(q)); 116.2 (CH), 111.2(CH); 110.8 (CH); 108.0 (CH); 107.7 (CH); 56.5 (CH₃); 56.4 (CH₃); 56.0(CH₃); 55.6 (CH₃); 26.6 (CH₂); 12.9 (CH₃) ppm.

MS (EI): m/z (%): (400.0 [M]⁺, 78), 385.0 ([M-CH₃]⁺, 100)

elemental analysis calcd (%) for C₂₂H₂₂O₆: C, 69.10; H, 5.80. Found C,69.20; H, 5.81.

12.15.6-fluoro-3-methyl-2-(4-(trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 65% (yellow needles)

m.p. (from hexane/EtOAc): 104-105° C.

¹H NMR (300 MHz, CDCl₃): δ=8.15 (dd, J=8.6 Hz, 5.3 Hz, 1H), 7.76 (dd,J=8.6 Hz, 2.8 Hz, 1H), 7.44 ((AB)₂ system, J=7.6 Hz, Δν=27.6 Hz, 4H),7.40-7.34 (m, 1H), 4.10 (s, 2H), 2.27 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.0 (C═O); 183.2 (C═O); 166.0 (d, J=244.0Hz, C_(q)); 145.0 (C_(q)); 144.6 (C_(q)); 142.0 (C_(q)); 134.6 (d, J=7.4Hz, C_(q)); 129.8 (d, J=9.0 Hz, CH); 128.9 (q, J=24.1 Hz C_(q)); 128.8(2×CH); 128.4 (C_(q)); 125.6 (q, J=4.0 Hz, 2×CH); 120.8 (d, J=21.9 Hz,CH); 113.1 (d, J=24.1 Hz, CH); 32.3 (CH₂); 13.6 (CH₃) ppm.

MS (EI): m/z (%): 349.0 [M+H⁺], 5), 333.0 [M-CH₃]⁺, 100)

elemental analysis calcd (%) for C₁₉H₁₂F₄O₂: C, 65.52; H, 3.47. Found C,65.38; H, 3.68.

12.16. 2-(4-bromobenzyl)-6-fluoro-3-methylnaphthalene-1,4-dione

Yield: 85% (yellow needles)

m.p. (from hexane/EtOAc): 107° C.

¹H NMR (300 MHz, CDCl₃): δ=8.14 (dd, J=8.6 Hz, 5.2 Hz, 1H), 7.75 (dd,J=8.6 Hz, 2.7 Hz, 1H), 7.35 (m, 1H), 7.26 ((AB)₂ system, J=7.6 Hz,Δν=27.6 Hz, 4H), 3.99 (s, 2H), 2.26 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.1 (C═O); 183.2 (C═O); 166.0 (d, J=254.0Hz, C_(q)); 145.0 (C_(q)); 144.7 (C_(q)); 136.8 (C_(q)); 134.7 (d, J=8.4Hz, C_(q)); 131.8 (2×CH); 130.3 (2×CH); 129.8 (d, J=8.9 Hz, CH); 128.5(C_(q)); 120.8 (d, J=24.0 Hz, CH); 120.4 (C_(q)); 113.0 (d, J=24.0 Hz,CH); 31.9 (CH₂); 13.3 (CH₃) ppm.

MS (EI): m/z (%): 358.0 ([M⁺], 17), 343.0 ([M-CH₃]⁺, 100) elementalanalysis calcd (%) for C₁₈H₁₂BrFO₂: C, 60.19; H, 3.37. Found C, 59.95;H, 3.67.

12.17.2-(3-chloro-4-fluorobenzyl)-6-fluoro-3-methylnaphthalene-1,4-dione

Yield: 45% yellow powder

m.p. (from hexane/EtOAc): 117-118° C.

¹H NMR (300 MHz, CDCl₃): δ=8.13 (dd, J=8.6 Hz, 5.3 Hz, 1H), 7.74 (dd,J=8.6 Hz, 2.7 Hz, 1H), 7.38 (td, J=8.3, 2.7 Hz, 1H), 7.10-7.01 (m, 3H),3.97 (s, 2H), 2.26 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.0 (d, J_(C-F)=1.0 Hz, C═O), 183.2 (C═O),166.1 (d, J_(C-F)=256.8 Hz, C_(q)), 156.9 (d, J_(C-F)=249.0 Hz, C_(q)),144.8 (d, J_(C-F)=1.7 Hz, C_(q)), 144.6 (C_(q)), 134.8 (d, J_(C-F)=3.3Hz, C_(q)), 134.6 (d, J_(C-F)=7.5 Hz, C_(q)), 130.5 (CH), 129.8 (d,J_(C-F)=9.4 Hz, CH), 128.5 (d, J_(C-F)=2.8 Hz, C_(q)), 128.3 (d,J_(C-F)=6.6 Hz, CH), 121.1 (d, J_(C-F)=18.0 Hz, C_(q)), 120.9 (d,J_(C-F)=22.4 Hz, CH), 116.7 (d, J_(C-F)=21.6 Hz, CH), 113.1 (d,J_(C-F)=23.4 Hz, CH), 31.5 (CH₂), 13.4 (CH₃) ppm.

MS (EI): m/z (%): 332.0 ([M⁺], 14), 317.0 ([M-CH₃]⁺, 100)

elemental analysis calcd (%) for C₁₈H₁₁ClF₂O₂: C, 64.98; H, 3.33. FoundC, 65.30; H, 3.68.

12.18.6-fluoro-2-(4-fluoro-3-(trifluoromethyl)benzyl)-3-methylnaphthalene-1,4-dione

Yield: 55% yellow powder

m.p. (from hexane/EtOAc): 106-107° C.

¹H NMR (300 MHz, CDCl₃): δ=8.13 (dd, J=8.6, 5.3 Hz, 1H), 7.74 (dd,J=8.6, 2.7 Hz, 1H), 7.38 (dd, J=6.6, 2.7 Hz, 1H), 7.43-7.35 (m, 2H),7.11 (t, J=9.2 Hz, 1H), 4.04 (s, 2H), 2.27 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=184.0 (d, J_(C-F)=1.3 Hz, C═O), 183.2 (C═O),166.1 (d, J_(C-F)=256.0 Hz, C_(q)), 158.5 (dq, J_(C-F)=254.8, 1.6 Hz,C_(q)), 144.9 (d, J_(C-F)=1.7 Hz, C_(q)), 144.4 (C_(q)), 134.6 (d,J_(C-F)=8.0 Hz, C_(q)), 134.1 (d, J_(C-F)=d, J_(C-F)=3.6 Hz, C_(q)),133.9 (d, J_(C-F)=7.8 Hz, CH), 129.9 (d, J_(C-F)=8.9, CH), 128.4 (d,J_(C-F)=3.3, C_(q)), 127.1 (dq, J_(C-F)=4.5, 1.6 Hz, CH), 124.2 (d,J_(C-F)=1.0 Hz, C_(q)), 120.9 (d, J_(C-F)=22.6 Hz, CH), 117.1 (d,J_(C-F)=20.7, CH), 113.1 (d, J_(C-F)=22.8, CH), 31.6 (CH₂), 13.4 (CH₃)ppm.

MS (EI): m/z (%): 366.0 ([M⁺], 26), 351.0 ([M-CH₃]⁺, 100)

elemental analysis calcd (%) for C₁₉H₁₁F₅O₂: C, 62.30; H, 3.03. Found C,62.31; H, 3.28.

12.19. 2,5-dimethyl-3-(4-(trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 63% (yellow needles)

m.p. (from hexane/EtOAc): 87-88° C.

¹H NMR (300 MHz, CDCl₃): δ=8.04 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.60-7.50(m, 2H), 7.46 ((AB)₂ system, J=7.5 Hz, Δν=55.2 Hz, 4H), 4.09 (s, 2H),2.74 (s, 3H), 2.23 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=186.3 (C═O); 185.5 (C═O); 145.6 (C_(q));143.2 (C_(q)); 142.4 (C_(q)); 141.2 (C_(q)); 137.6 (CH); 133.5 (C_(q));132.7 (CH); 129.7 (C_(q)); 128.8 (2×CH); 128.7 (q, J=31 Hz, C_(q)),125.5 (q, J=3.8 Hz, 2×CH); 124.2 (q, J=273.0 Hz, CF₃); 125.3 (CH); 32.5(CH₂); 22.9 (CH₃); 13.1 (CH₃) ppm.

MS (EI): m/z (%): 344.2 ([M⁺], 33), 329.2 ([M⁺-CH₃], 100)

elemental analysis calcd (%) for C₂₀H₁₅F₃O₂: C, 69.76; H, 4.39. Found C,69.49; H, 4.54.

12.20. 3-(4-bromobenzyl)-2,5-dimethylnaphthalene-1,4-dione

Yield: 75% (yellow needles)

m.p. (from hexane/EtOAc): 149-150° C.

¹H NMR (300 MHz, CDCl₃): δ=8.03 (dd, J=7.5 Hz, 1.5 Hz 1H), 7.59-7.49 (m,2H), 7.27 ((AB)₂ system, J=7.4 Hz, Δν=81.3 Hz, 4H), 3.96 (s, 2H), 2.76(s, 3H), 2.29 (s, 3H)

¹³C NMR (75 MHz, CDCl₃): δ=186.4 (C═O); 185.6 (C═O); 146.0 (C_(q));142.9 (C_(q)); 141.1 (C_(q)); 137.6 (CH); 137.3 (C_(q)); 133.2 (C_(q));132.6 (CH); 131.7 (2×CH); 130.2 (2×CH); 129.7 (C_(q)); 125.2 (CH); 120.2(C_(q)); 32.1 (CH₂); 22.9 (CH₃); 13.1 (CH₃) ppm.

MS (EI): m/z (%) 355.03 ([M⁺], 100), 356.04 ([M+H⁺], 18),

elemental analysis calcd (%) for C₁₉H₁₅BrO₃: C, 64.24; H, 4.26. Found C,64.01; H, 4.33.

12.21. 3-(4-bromobenzyl)-2,6-dimethylnaphthalene-1,4-dione

Yield: 50% (yellow needles)

¹H NMR (300 MHz, CDCl₃): δ=7.98 (d, J=7.9 Hz, 1H), 7.87 (s, 1H), 7.50(d, J=7.9 Hz, 1H) 7.38, (d, J=8.4 Hz, 2H), 7.11 (d, J=7.4, 2H), 3.96 (s,2H),), 2.48 (s, 3H) 2.23 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=185.1 (C═O); 184.9 (C═O); 144.7 (C_(quat));144.5 (C_(quat)); 137.2 (C_(quat)); 134.3 (CH); 131.8 (C_(quat)); 131.7(2×CH); 130.3 (2×CH); 129.9 (C_(quat)) 126.8 (CH); 126.5 (CH); 120.3(C_(quat)); 31.9 (CH₂); 21.9 (CH₃) 13.3 (CH₃) ppm

MS (EI): m/z (%): 354.1 ([M⁺], 18), 341 (78), 339.1 ([M⁺-CH₃], 100),260.1 (43),

elemental analysis calcd (%) for C₁₉H₁₅BrO₂: C, 64.24; H, 4.26. Found C,64.15; H, 4.27.

m.p. 103-104° C.

12.22. 2,6-dimethyl-3-(4-(trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 65% (yellow needles)

¹H NMR (300 MHz, CDCl₃): δ=7.98 (d, J=7.4 Hz, 1H), 7.87 (s, 1H),7.53-7.48 (m, 3H), 7.17 (d, J=7.4, 2H), 4.07 (s, 2H),), 2.48 (s, 3H)2.23 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=185.0 (C═O); 184.8 (C═O); 144.8 (C_(quat));144.7 (C_(quat)); 144.2 (C_(quat)); 144.4 (C_(quat)); 134.4 (CH); 131.8(C_(quat)); 128.9 (2×CH); 126.9 (CH); 129.9 (C_(quat)) 126.6 (CH); 125.6(q, J=3.8 Hz 2×CH), 122.3 (C_(quat)); 32.3 (CH₂); 21.8 (CH₃) 13.3 (CH₃)ppm

MS (EI): m/z (%): 344.2 ([M⁺], 30), 329.2 ([M⁺-CH₃], 100), 372. 2 (19)

elemental analysis calcd (%) for C₂₀H₁₅F₃O₂: C, 69.76; H, 4.39. Found C,69.57; H, 4.44.

m.p. 93-94° C.

12.23. 2,7-dimethyl-3-(4-(trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 68% (yellow needles)

m.p. (from hexane/EtOAc): 102° C.

¹H NMR (300 MHz, CDCl₃): δ=7.98 (d, J=7.1 Hz, 1H), 7.88 (s, 1H), 7.51(d, J=7.1 Hz, 1H), 7.44 ((AB)₂ system, J=7.3 Hz, Δν=52.0 Hz, 4H), 4.08(s, 2H), 2.49 (s, 3H), 2.24 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=185.4 (C═O); 184.4 (C═O); 144.8 (C_(q));144.6 (C_(q)); 144.3 (C_(q)); 142.3 (C_(q)); 134.4 (CH); 130.0 (C_(q));129.0 (C_(q)); 128.7 (q, J=31 Hz, C_(q)), 126.8 (2×CH) 125.5 (q, J=3.8Hz, 2×CH); 124.1 (q, J=275.0 Hz, CF₃); 32.3 (CH₂); 21.8 (CH₃); 13.3(CH₃) ppm.

MS (EI): m/z (%): 345.11 ([M⁺], 100), 346.11 ([M+H⁺], 25), elementalanalysis calcd (%) for C₂₀H₁₅F₃O₂: C, 69.76; H, 4.39. Found C, 69.42; H,4.49.

12.24. 2,7-dimethyl-3-(4-bromobenzyl)naphthalene-1,4-dione

Yield: 70% (yellow needles)

m.p. (from hexane/EtOAc): 122-123° C.

¹H NMR (300 MHz, CDCl₃): δ=7.97 (d, J=7.9 Hz, 1H), 7.88 (s, 1H), 7.50(d, J=7.9 Hz, 1H), 7.24 ((AB)₂ system, J=8.5 Hz, Δν=83.3 Hz, 4H), 4.08(s, 2H), 2.49 (s, 3H), 2.24 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=185.5 (C═O); 184.8 (C═O); 144.4 (C_(q));144.2 (C_(q)); 143.3 (C_(q)); 137.3 (C_(q)); 131.6 (2×CH); 130.3 (2×CH);130.1 (C_(q)); 129.9 (C_(q)); 127.5 (CH); 127.3 (CH); 120.2 (C_(q));31.8 (CH₂); 20.2 (CH₃); 13.2 (CH₃) ppm.

MS (EI): m/z (%): 355.03 ([M⁺], 100), 356.04 ([M+H⁺], 25),

elemental analysis calcd (%) for C₁₉H₁₅BrO₃: C, 64.24; H, 4.26. Found C,64.05; H, 4.33.

12.25. 2,8-dimethyl-3-(4-(trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 75% (yellow needles)

m.p. (from hexane/EtOAc): 98-99° C.

¹H NMR (300 MHz, CDCl₃): δ=7.99 (dd, J=7.5 Hz, 1.2 Hz, 1H), 7.50-7.41(m, 2H), 7.35 ((AB)₂ system, J=7.5 Hz, Δν=52.3 Hz, 4H), 3.98 (s, 2H),2.66 (s, 3H), 2.15 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=187.0 (C═O); 184.9 (C═O); 146.2 (C_(q));142.8 (C_(q)); 142.4 (C_(q)); 142.3 (C_(q)); 137.6 (CH); 133.5 (C_(q));132.7 (CH); 129.7 (C_(q)); 128.8 (2×CH); 128.7 (q, J=31 Hz, C_(q));125.5 (q, J=3.8 Hz, 2×CH); 124.2 (q, J=273.0 Hz, CF₃); 125.3 (CH); 32.5(CH₂); 22.9 (CH₃); 13.1 (CH₃) ppm.

MS (EI): m/z (%): 344.2 ([M⁺], 28), 329.2 ([M⁺-CH₃], 100)

elemental analysis calcd (%) for C₂₀H₁₅F₃O₂: C, 69.76; H, 4.39. Found C,69.69; H, 4.53.

12.26. 2,8-dimethyl-3-(4-bromobenzyl)naphthalene-1,4-dione

Yield: 67% (yellow needles)

m.p. (from hexane/EtOAc): 116-118° C.

¹H NMR (300 MHz, CDCl₃): δ=8.03 (dd, J=7.5 Hz, 1.5 Hz 1H), 7.59-7.49 (m,2H), 7.27 ((AB)₂ system, J=8.0 Hz, Δν=40.9 Hz, 4H), 3.98 (s, 2H), 2.74(s, 3H), 2.22 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=187.1 (C═O); 185.0 (C═O); 145.9 (C_(q));143.1 (C_(q)); 141.0 (C_(q)); 137.5 (CH); 137.2 (C_(q)); 133.4 (C_(q));132.7 (CH); 131.7 (2×CH); 130.3 (2×CH); 129.8 (C_(q)); 125.4 (CH); 120.3(C_(q)); 32.1 (CH₂); 22.9 (CH₃); 13.1 (CH₃) ppm.

MS (EI): m/z (%) 355.03 ([M⁺], 100), 356.04 ([M+H⁺], 27),

elemental analysis calcd (%) for C₁₉H₁₅BrO₃: C, 64.24; H, 4.26. Found C,64.19; H, 4.37.

12.27.2,6,7-trimethyl-3-(4-(trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 87% (yellow needles)

m.p. (from hexane/EtOAc): 143-144° C.

¹H NMR (300 MHz, CDCl₃): δ=7.84 (s, 3H), 7.86 (s, 3H), 7.44 ((AB)₂system, J=8.5 Hz, Δν=44.0 Hz, 4H), 4.07 (s, 2H), 2.74 (s, 3H), 2.40 (s,3H), 2.39 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=185.2 (C═O); 184.7 (C═O); 144.5 (C_(q));144.0 (C_(q)); 143.5 (C_(q)); 143.4 (C_(q)); 142.4 (C_(q)); 130.1(C_(q)); 129.9 (C_(q)); 128.9 (2×CH); 128.7 (q, J=31.9 Hz, C_(q)); 127.5(CH); 127.4 (CH); 125.5 (q, J=3.8 Hz, 2×CH); 124.1 (q, J=270.7 Hz, CF₃);32.3 (CH₂); 20.2 (2×CH₃); 13.1 (CH₃) ppm.

MS (EI): m/z (%): 358.1 ([M⁺], 26), 343.1 ([M⁺-CH₃], 100)

elemental analysis calcd (%) for C₂₁H₁₇F₃O₂: C, 70.38; H, 4.78. Found C,70.32; H, 4.96.

12.28. 2,6,7-trimethyl-3-(4-bromobenzyl)naphthalene-1,4-dione

Yield: 82% (yellow needles)

m.p. (from hexane/EtOAc): 129-130° C.

¹H NMR (300 MHz, CDCl₃): δ=7.82 (s, 2H), 7.25 ((AB)₂ system, J=8.2 Hz,Δν=73.9 Hz, 4H), 3.98 (s, 2H), 2.39 (s, 6H), 2.22 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=187.1 (C═O); 185.0 (C═O); 145.9 (C_(q));143.1 (C_(q)); 141.0 (C_(q)); 137.5 (CH); 137.2 (C_(q)); 133.4 (C_(q));132.7 (CH); 131.7 (2×CH); 130.3 (2×CH); 129.8 (C_(q)); 125.4 (CH); 120.3(C_(q)); 32.1 (CH₂); 22.9 (CH₃); 13.1 (CH₃) ppm.

MS (EI): m/z (%): 368.1 ([M⁺], 26), 353.0 ([M⁺-CH₃], 100) elementalanalysis calcd (%) for C₂₀H₁₇BrO₂: C, 65.05; H, 4.64. Found C, 64.66; H,4.71.

12.29.6-methyl-5,8-dioxo-7-(4-(trifluoromethyl)benzyl)-5,8-dihydronaphthalen-2-yltrifluoromethanesulfonate

Yield: 70% (yellow needles)

m.p. (from hexane/EtOAc): 127° C.

¹H NMR (300 MHz, CDCl₃): δ=8.16 (d, J=8.6 Hz, 1H), 7.90 (d, J=2.7 Hz,1H) 7.53 (dd, J=8.6 Hz, 2.7 Hz, 1H), 7.38 ((AB)₂ system, J=8.2 Hz,Δν=57.0 Hz, 4H), 4.03 (s, 2H), 2.21 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=183.4 (C═O); 182.6 (C═O); 152.9 (C_(q));145.0 (C_(q)); 141.6 (C_(q)); 141.6 (C_(q)); 134.0 (C_(q)); 131.4(C_(q)); 129.4 (2×CH); 129.1 (q, J=33.1 Hz, C_(q)), 129.0 (CH); 128.0(CH); 126.4 (CH), 125.5 (q, J=3.8 Hz, 2×CH); 124.1 (q, J=281.1 Hz, CF₃);119.3 (CH); 118.7 (q, J=315.5 Hz, S—CF₃); 32.4 (CH₂); 13.4 (CH₃) ppm.

MS (EI): m/z (%): 478.0 ([M⁺], 23), 463.0 ([M⁺-CH₃], 100)

elemental analysis calcd (%) for C₂₀H₁₂F₆O₅S: C, 50.22; H, 2.83. FoundC, 50.13; H, 2.84.

12.30.7-methyl-5,8-dioxo-6-(4-(trifluoromethyl)benzyl)-5,8-dihydronaphthalen-2-yltrifluoromethanesulfonate

Yield: 75% (yellow needles)

m.p. (from hexane/EtOAc): 87-88° C.

¹H NMR (300 MHz, CDCl₃): δ=8.15 (d, J=8.6 Hz, 1H), 7.91 (d, J=2.5 Hz,1H) 7.53 (dd, J=8.6 Hz, 2.5 Hz, 1H), 7.33 ((AB)₂ system, J=8.2 Hz,Δν=49.0 Hz, 4H), 4.02 (s, 2H), 2.21 (s, 3H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=183.2 (C═O); 182.8 (C═O); 152.9 (C_(q));145.2 (C_(q)); 145.2 (C_(q)); 144.9 (C_(q)); 134.2 (C_(q)); 129.6 (CH);129.1 (q, J=31.4 Hz, C_(q)); 128.7 (2×CH); 126.4 (CH); 125.7 (q, J=3.8Hz, 2×CH), 124.0 (q, J=275.8 Hz, CF₃); 119.2 (CH); 118.7 (q, J=319.9 Hz,S—CF₃); 32.4 (CH₂); 13.5 (CH₃) ppm.

MS (EI): m/z (%): 478.0 ([M⁺], 20), 463.0 ([M⁺-CH₃], 100)

elemental analysis calcd (%) for C₂₀H₁₂F₆O₅S: C, 50.22; H, 2.83. FoundC, 50.27; H, 2.79.

EXAMPLE 13 General Procedure for the Synthesis of HydroxymenadioneDerivatives by Triflate Deprotection

To a solution of trifluoromethanesulfonic ester (1 eq) in THF (0.2M),TBAF×3H₂O (3 eq) was added. The mixture was stirred for 3 h, dilutedwith EtOAc (10 mL) and the THF was evaporated. The mixture wasneutralized with 1 N aqueous HCl solution. The organic layer was driedover anhydrous MgSO₄, concentrated in vacuo and purified by columnchromatography EtOAc/Cyclohexane 4:1 to give the hydroxynaphthoquinone.

13.16-hydroxy-3-methyl-2-(4-(trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 70% (yellow needles)

m.p. (from hexane/EtOAc): >200° C. dec.

¹H NMR (400 MHz, DMSO): δ=10.81 (bs, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.61((AB)₂ system, J=8.9 Hz, Δν=53.0 Hz, 4H), 7.30 (d, J=2.5 Hz, 1H) 7.13(dd, J=8.5 Hz, 2.6 Hz, 1H), 4.03 (s, 2H), 2.10 (s, 3H) ppm.

¹³C NMR (100 MHz, DMSO): δ=184.7 (C═O); 183.8 (C═O); 163.1 (C_(q));145.1 (C_(q)); 143.8 (C_(q)); 143.5 (C_(q)); 134.1 (C_(q)); 129.5(2×CH); 129.4 (CH); 127.3 (q, J=31.4 Hz, C_(q)); 125.8 (q, J=3.9 Hz,2×CH), 124.8 (q, J=275.6 Hz, C_(q)); 121.1 (CH); 111.7 (CH); 32.1 (CH₂);13.5 (CH₃) ppm.

MS (EI): m/z (%): 346.04 ([M⁺], 100), 357.04 ([M+H⁺], 15),

elemental analysis calcd (%) for C₁₉H₁₃F₃O₃C, 65.90; H, 3.78. Found C,65.73; H, 3.85.

13.27-hydroxy-3-methyl-2-(4-(trifluoromethyl)benzyl)naphthalene-1,4-dione

Yield: 60% (yellow needles)

m.p. (from hexane/EtOAc): >200° C., dec.

¹H NMR (300 MHz, DMSO): δ=10.81 (bs, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.44((AB)₂ system, J=8.9 Hz, Δν=53.0 Hz, 4H), 7.31 (d, J=2.6 Hz, 1H) 7.14(dd, J=8.5 Hz, 2.6 Hz, 1H), 4.05 (s, 2H), 2.12 (s, 3H) ppm.

¹³C NMR (75 MHz, DMSO): δ=184.8 (C═O); 182.8 (C═O); 162.6 (C_(q)); 144.1(C_(q)); 143.6 (C_(q)); 143.4 (C_(q)); 143.3 (CH); 133.8 (C_(q)); 129.1(2×CH); 129.0 (CH); 126.8 (q, J=31.6 Hz, C_(q)); 125.6 (q, J=3.8 Hz,2×CH); 124.2 (q, J=275.9 Hz, CF₃); 120.3 (CH); 111.6 (CH); 31.5 (CH₂);12.9 (CH₃) ppm.

MS (EI): m/z (%): 346.1 ([M+], 32), 331.0 ([M⁺-CH₃], 100)

elemental analysis calcd (%) for C₁₉H₁₃F₃O₃C, 65.90; H, 3.78. Found C,66.13; H, 3.67.

EXAMPLE 14 General Procedure for the Synthesis of Compounds Ia4

The corresponding azamenadione derivatives, compounds of formula (II),(1 eq, 0.05 mmol·mL⁻¹) and a phenyl acetic acid derivative (compounds offormula (III)) (2 eq) were added to a stirred solution of MeCN/H₂O (3/1)and heated at 85° C. (70° C. in the flask). AgNO₃ (0.35 eq) was addedfirst and then (NH₄)₂S₂O₈ (1.3 eq, 0.36 mmol·mL⁻¹) in MeCN/H₂O (3/1) wasadded dropwise. The reaction mixture was then heated 2-3 hours at 85° C.MeCN was evaporated and the mixture was extracted with DCM. The crudemixture was purified by flash chromatography on silica gel using amixture diethyl ether and toluene (70/30). When necessary, the compoundwas further purified by trituration in diethyl ether.

14.1. 6-(4-bromobenzyl)-7-methylquinoline-5,8-dione

Yield: 33%

m.p. 105-106° C.

¹H NMR (300 MHz, CDCl₃): δ=9.02 (s, 1H), 8.43 (d, J=7.5 Hz, 1H),7.64-7.66 (d, J=6.1 Hz, 1H), 7.26 ((AB)₂ system, J=8.3 Hz, Δν=72.4 Hz,4H), 4.05 (s, 2H), 2.27 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=184.7 (C═O), 183.0 (C═O), 154.6 (CH), 147.4(C_(q)), 145.9 (C_(q)), 144.1 (C_(q)), 136.5 (C_(q)), 134.5 (CH), 131.8(2×CH), 130.6 (2×CH), 128.9 (C_(q)), 127.6 (CH), 120.5 (C_(q)), 32.0(CH₂), 13.3 (CH₃) ppm

EI MS (70 eV, m/z (%)): 341.0 ([M]⁺, 17), 325.9 ([M-CH₃]⁺, 57),

elemental analysis calcd. for C₁₇H₁₂BrNO₂: C, 59.67; H, 3.53; N, 4.09;Br, 23.35. Found: C, 59.57; H, 3.65; N, 4.02; Br, 23.13.

14.2. 6-(2,5-dimethoxybenzyl)-3,7-dimethylquinoline-5,8-dione

Yield: 58%

m.p.: 133-135° C.

¹H NMR (300 MHz, CDCl₃): δ=8.81 (d, J=2.1 Hz, 1H), 8.18 (d, J=2.1 Hz,1H), 6.77-6.66 (m, 3H), 4.05 (s, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 2.51(s, 3H), 2.18 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=184.3 (C═O), 183.7 (C═O), 154.8 (CH), 153.5(C_(q)), 151.5 (C_(q)), 145.8 (C_(q)), 145.5 (C_(q)), 144.9 (C_(q)),138.3 (C_(q)), 134.4 (CH), 128.6 (C_(q)), 127.2 (C_(q)), 116.3 (CH),111.2 (CH), 111.1 (CH), 55.9 (CH₃), 55.6 (CH₃), 26.9 (CH₂), 18.9 (CH₃),13.2 (CH₃) ppm

EI MS (70 eV, m/z (%)): 337.13 ([M]⁺, 65), 322.1 ([M-CH₃]⁺, 100);

elemental analysis calcd. for C₂₀H₁₉NO₄: C, 71.20; H, 5.68; N, 4.15.Found: C, 71.35; H, 5.75; N, 4.20.

14.3. 6-(4-bromobenzyl)-3,7-dimethylquinoline-5,8-dione

Yield: 50%

m.p.: 146-148° C. (Et₂O)

¹H NMR (300 MHz, CDCl₃): δ=8.83 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz,1H), 7.26 ((AB)₂ system, J=8.0 Hz, Δν=72.4 Hz, 4H), 4.04 (s, 2H), 2.52(s, 3H), 2.26 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=185.0 (C═O), 182.9 (C═O), 155.1 (CH), 145.7(C_(q)), 145.3 (C_(q)), 143.8 (C_(q)), 138.5 (C_(q)), 136.6 (C_(q)),134.2 (CH), 131.7 (2×CH), 130.5 (2×CH), 128.5 (C_(q)), 120.4 (C_(q)),31.9 (CH₂), 18.9 (CH₃), 13.2 (CH₃) ppm

elemental analysis calcd. for C₁₈H₁₄BrNO₂: C, 60.69; H, 3.96; N, 3.93;Br, 22.43. Found: C, 60.92; H, 4.02; N, 3.89; Br, 22.28.

14.4. 6-(3,5-dimethoxybenzyl)-3,7-dimethylquinoline-5,8-dione

3,7-dimethylquinoline-5,8-dione (250 mg, 1.34 mmol, 1 equiv.) and2-(3,5-dimethoxyphenyl)acetic acid (524.08 mg, 2.67 mmol, 2 equiv) gavea mixture which was purified by column chromatography using diethylether and toluene (70/30) to give a yellow solid.

This solid was triturated in diethyl ether, filtrated and dried undervacuum to afford 22 (160 mg, 0.47 mmol, 35%).

m.p.: 106-108° C. (Et₂O)

¹H NMR (300 MHz, CDCl₃): δ=8.83 (d, J=2.1 Hz, 1H), 8.20 (d, J=2.1 Hz,1H), 6.41-6.29 (m, 3H), 4.03 (s, 2H), 3.74 (s, 6H), 2.52 (s, 3H), 2.27(s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=185.1 (C═O), 182.9 (C═O), 160.9 (C_(q)),155.0 (CH), 145.9 (C_(q)), 145.3 (C_(q)), 143.9 (C_(q)), 139.8 (C_(q)),138.4 (C_(q)), 134.2 (CH), 128.5 (CH), 107.0 (C_(q)), 98.3 (C_(q)), 32.5(CH₂), 18.8 (CH₃), 13.2 (CH₃) ppm

EI MS (70 eV, m/z (%)): 337.0 ([M]⁺, 41), 322.0 ([M-CH₃]⁺, 100)

elemental analysis calcd. for C₂₀H₁₉NO₄: C, 71.20; H, 5.68; N, 4.15.Found: C, 70.85; H, 5.70; N, 4.15.

analysis calcd. for C₂₀H₁₉NO₄: C, 71.20; H, 5.68; N, 4.15. Found: C,70.85; H, 5.70; N, 4.15.

14.5. 3,7-dimethyl-6-(4-(trifluoromethyl)benzyl)quinoline-5,8-dione

3,7-dimethylquinoline-5,8-dione (250 mg, 1.34 mmol, 1 equiv.) and2-(4-(trifluoromethyl)phenyl)acetic acid (545.39 mg, 2.67 mmol, 2equiv.) gave a mixture which was purified by column chromatography usingdiethyl ether and toluene (80/20) to give a brown solid.

This solid was triturated in diethyl ether, filtrated and dried undervacuum to afford the final compound (230 mg, 0.66 mmol, 50%).

m.p.: 121-123° C. (Et₂O)

¹H NMR (300 MHz, CDCl₃): δ=8.83 (s, 1H), 8.21 (s, 1H), 7.45 ((AB)₂system, J=7.8 Hz, Δν=41.9 Hz), 4.14 (s, 2H), 2.52 (s, 3H), 2.27 (s, 3H)ppm

¹³C NMR (75 MHz, CDCl₃): δ=184.9 (C═O), 182.9 (C═O), 155.2 (CH), 145.3(C_(q)), 145.2 (C_(q)), 141.7 (C_(q)), 143.2 (CH), 138.6 (C_(q)), 129.1(2×CH), 128.9 (q, J_(C-F)=25.6 Hz, C_(q)), 128.5 (C_(q)), 125.6 (q,J_(C-F)=3.7 Hz, 2×CH), 124.0 (q, J_(C-F)=272.6 Hz, C_(q)), 32.3 (CH₂),18.9 (CH₃), 13.3 (CH₃) ppm

EI MS (70 eV, m/z (%)): 345.0 ([M]⁺, 41), 330.0 ([M-CH₃]⁺, 100)

elemental analysis calcd. for C₁₉H₁₄F₃NO₂: C, 66.09; H, 4.09; F, 16.51;N, 4.06. Found: C, 66.15; H, 4.12; N, 4.08.

14.6. 7-methyl-6-(4-(trifluoromethyl)benzyl)quinoline-5,8-dione

Yield: 51%

¹H NMR (300 MHz, CDCl₃): δ=8.95 (dd, J=4.7 Hz, 1.7 Hz, 1H), 8.36 (dd,J=7.9 Hz, 1.7 Hz, 1H), 7.59 (dd, J=7.9 Hz, 4.7 Hz, 1H), 7.38 ((AB)₂system, J=8.5 Hz, Δν=41.5 Hz, 4H), 4.08 (s, 2H), 2.21 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=184.0 (C═O), 182.9 (C═O), 154.6 (CH), 147.4(C_(q)), 145.5 (C_(q)), 144.3 (C_(q)), 134.5 (CH), 129.1 (2×CH), 127.6,(CH), 128.7 (C_(q)), 127.6 (CH), 125.6 (q, J=3.8 Hz, 2×CH); 122.2(C_(q)), 32.3 (CH₂), 13.7 (CH₃) ppm

MS (EI): m/z (%): 331.0 ([M]⁺, 41), 316.1 ([M-CH₃]⁺, 100)

elemental analysis calcd (%) for C₁₈H₁₂F₃NO₂: C, 65.26; H, 3.65; N,4.23. Found C, 65.28; H, 3.71; N, 4.23.

m.p. 107-109° C.

14.7. 6-(2,5-dimethoxybenzyl)-7-methylquinoline-5,8-dione

Yield: 45%

¹H NMR (300 MHz, CDCl₃): δ=9.02 (dd, J=4.7 Hz, J=1.7 Hz, 1H), 8.44 (dd,J=7.9 Hz, J=1.7 Hz, 1H), 7.66 (dd, J=7.8 Hz, J=4.7 Hz, 1H), 6.80-6.70(m, 3H), 4.08 (s, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 2.80 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=184.9 (C═O), 183.0 (C═O), 154.3 (CH), 153.6(C_(q)), 151.5 (C_(q)), 147.8 (C_(q)), 146.6 (C_(q)), 144.4 (C_(q)),134.4 (CH), 129.0 (C_(q)), 127.3 (CH), 127.1 (C_(q)), 116.5 (CH), 111.6(CH), 111.3 (CH), 56.0 (CH₃), 55.7 (CH₃), 27.1 (CH₂), 13.1 (CH₃) ppm

EI MS (70 eV, m/z (%)): 323.2 ([M]⁺, 53), 308.1 ([M-CH₃]⁺, 100), 293.1(43),

elemental analysis calcd. for C₁₉H₁₇NO₄.0.45H₂O: C, 68.85; H, 5.44; N,4.23. Found: C, 68.25; H, 5.30; N, 4.28.

m.p. 135-137° C.

14.8. 6-(3,5-dimethoxybenzyl)-7-methylquinoline-5,8-dione

Yield: 55%

¹H NMR (300 MHz, CDCl₃): δ=9.02 (dd, J=4.7 Hz, J=1.7 Hz, 1H), 8.44 (dd,J=7.9 Hz, J=1.7 Hz, 1H), 7.66 (dd, J=7.8 Hz, J=4.7 Hz, 1H), 6.41 (d,J=2.2 Hz, 2H), 6.29 (t, J=2.2 Hz, 1H), 4.04 (s, 2H), 3.75 (s, 6H),δ=2.33 (s, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=184.8 (C═O), 183.0 (C═O), 160.9 (C_(q)),154.4 (CH), 147.5 (C_(q)), 146.0 (C_(q)), 144.1 (C_(q)), 139.7 (C_(q)),134.4 (CH), 128.9 (C_(q)), 127.5 (CH), 107.4 (2×CH), 98.3 (CH), 55.3(2×OCH₃), 32.6 (CH₂), 13.3 (CH₃) ppm

EI MS (70 eV, m/z (%)): 323.2 ([M]⁺, 42), 308.1 ([M-CH₃]⁺, 100), 166.1(77), 293.1 (58), 173.0 (53), 166.1 (77).

elemental analysis calculated for C₁₉H₁₇NO₄: C, 70.58; H, 5.30; N, 4.33.Found: C, 70.30; H, 5.41; N, 4.26.

EXAMPLE 15 Synthesis of Azamenadiones (Compounds IIa4)7-methylquinoline-5,8-dione (R═H) 3,7-dimethylquinoline-5,8-dione (R=Me)

(E)-1,1-dimethyl-2-(2-methylallylidene)hydrazine (2.18 g, 19.50 mmol,1.3 equiv.) and acetic anhydride (19.15 mL) were added in 250 mL of MeCNand stirred at room temperature.2-bromo-5-methylcyclohexa-2,5-diene-1,4-dione (3 g, 14.9 mmol, 1 equiv.)in 125 mL of MeCN was then added dropwise (slowly during 60 min). Thereaction mixture was stirred at room temperature during 120 minutes.

The crude was then concentrated and purified by column chromatographyusing diethyl ether and toluene (80/20) to give a brown solid.

This solid was triturated in diethyl ether, filtrated and dried undervacuum to give 452 mg, 2.41 mmol, 16%)

m.p.: 178-180° C.

¹H NMR (300 MHz, CDCl₃): δ=8.85 (s, 1H), 8.22 (s, 1H), 6.97-6.98 (d,⁴J=1.5 Hz, 1H), 2.53 (s, 3H), 2.22-2.23 (d, ⁴J=1.5 Hz, 3H) ppm

¹³C NMR (75 MHz, CDCl₃): δ=184.56 (C═O), 183.68 (C═O), 155.09 (CH),149.04 (C_(q)), 145.63 (C_(q)), 138.65 (C_(q)), 134.86 (CH), 133.94(CH), 128.67 (C_(q)), 18.86 (CH₃), 16.69 (CH₃) ppm

elemental analysis calculated for C₁₁H₉NO₂: C, 70.58; H, 4.85; N, 7.48.Found: C, 70.27; H, 4.74; N, 7.26.

EXAMPLE 16 Synthesis of Compound of Formula (XXIII) 16.1. Condensationof the 2-bromo-1.4-dimethoxy-3-methylnaphthalene derivative and astarting benzoylchloride derivative

General Procedure:

The 2-bromo-1,4-dimethoxy-3-methylnaphthalene derivative (Bauer H,Fritz-Wolf K, Winzer A, Kühner S, Little S, Yardley V, Vezin H, PalfeyB, Schirmer R H, Davioud-Charvet E. J Am Chem. Soc. 2006, 128:10784-94)(1.0 equiv.) was placed in an Argon flushed flask. Dry THF was added andthe mixture was cooled to −78° C. BuLi (1.1 equiv.) was added dropwiseand the mixture was stirred 10 min at −78° C. Then, the benzoylchloride(1.1 equiv.) was added under stirring and the reaction mixture wasstirred at −78° C. for 30 min. The reaction mixture was then allowed towarm to RT. The mixture was poured into a 20 mL 1:1 mixture of dilutedHCl:saturated NaCl and it was extracted twice with 20 mL Et₂O. Theorganic phase was dried over MgSO₄ and evaporated. The resulting oil waspurified through flash chromatography.

16.1.1. (1.4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluorophenyl)methanoneLJ103

2-bromo-1,4-dimethoxy-3-methylnaphthalene (500 mg. 1.78 mmol) andcommercially available 2-fluorobenzoylchloride (307 mg. 1.96 mmol) weretreated according to general procedure 12.1. The resulting orange oilwas purified through flash chromatography (Cyclohexane:EtOAc 10:1). Theproduct was obtained as a white powder. Rf(Cyclohexane:EtOAc 10:1)=0.28.Yield=295 mg (51%).

¹H NMR (300 MHz, CDCl₃): δ=8.03-8.06 (m, 1H), 7.95-7.98 (m, 1H), 7.68(cm, 1H), 7.39-7.51 (m, 3H), 7.12 (cm, 1H), 7.02 (ddd, ³J_(HF)=11 Hz,³J_(HH)=8 Hz, ⁴J_(HH)=1 Hz, 1H), 3.82 (s, 3H), 3.72 (s, 3H, OCH₃), 2.22(s, 3H, OCH₃) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=194.34 (C═O), 161.93 (d. ¹J_(CF)=260 Hz.Cq-F), 150.50 (Cq-O), 149.31 (Cq-O), 135.05 (CHar), 132.54 (Cq), 131.58(CHar), 129.50 (Cq), 127.15 (CHar), 126.87 (Cq), 126.75 (Cq), 125.93(CHar), 124.32 (CHar), 123.41 (Cq), 122.68 (CHar), 122.45 (CHar), 116.97(CHar-F), 63.48 (OCH₃), 61.51 (OCH₃), 12.73 (CH₃) ppm.

¹⁹F NMR (282 MHz, CDCl₃): δ=−111.81 (cm, ³J_(HF)=11 Hz, ⁴J_(HF)=7 Hz)

EA calcd for C₂₀H₁₇O₃F (%): C, 74.06; H, 5.28; O, 14.80. Found: C,73.76; H, 5.40.

Mp=133-135°

16.1.2.(1.4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluoro-3-trifluoromethyl)phenyl)methanone LJ116

2-bromo-1.4-dimethoxy-3-methylnaphthalene (100 mg. 0.356 mmol) andcommercially available 2-fluoro-3-trifluoromethyl-benzoylchloride (90mg. 0.392 mmol) were treated according to general procedure 12.1. Theresulting brown oil was purified through flash chromatography(Cyclohexane:EtOAc 10:1). The product was obtained as yellow oil.Rf(Cyclohexane:EtOAc 10:1)=0.35. Yield=45 mg (32%).

¹H NMR (300 MHz, CDCl₃): δ=8.13-8.15 (m, 1H). 8.03-8.05 (m, 1H).7.92-7.98 (m, 1H). 7.79-7.83 (m, 1H). 7.50-7.62 (cm, 2H), 7.31-7.36 (m,1H). 3.92 (s, 3H, OCH₃). 3.79 (s, 3H, OCH₃). 2.33 (s, 3H, CH₃) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=193.18 (C═O), 159.01 (d. ¹J_(CF)=269 Hz.Cq-F), 150.69 (Cq-O), 149.83 (Cq-O), 137.21 (CHar), 135.06 (CHar),133.43 (Cq), 131.64 (Cq), 131.51 (CHar), 128.50 (Cq), 128.43 (q.¹J_(CF)=259 Hz. CF₃), 128.38 (Cq), 127.52 (CHar), 126.13 (CHar), 124.40(Cq), 124.18 (CHar), 123.32 (Cq), 122.62 (CHar), 63.55 (OCH₃), 61.57(OCH₃), 12.77 (CH₃) ppm.

EI MS (70 eV, m/z (%): 392.0 ([M+], 25)

16.1.3.(1.4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluoro-4-(trifluoromethyl)phenyl)methanone LJ123

2-bromo-1.4-dimethoxy-3-methylnaphthalene (300 mg, 1.07 mmol) andcommercially available 2-fluoro-4-trifluoromethyl-benzoylchloride (265mg. 1.17 mmol) were treated according to general procedure 12.1. Theresulting yellow oil was purified through flash chromatography(Cyclohexane:EtOAc 10:1). The product was obtained as a yellow oil.Rf(Cyclohexane:EtOAc 10:1)=0.50. Yield=175 mg (42%).

¹H NMR (300 MHz, CDCl₃): δ=8.13-8.15 (m, 1H). 8.03-8.05 (m, 1H).7.92-7.98 (m, 1H). 7.79-7.83 (m, 1H). 7.50-7.62 (cm, 2H), 7.31-7.36 (m,1H). 3.92 (s, 3H, OCH₃). 3.79 (s, 3H, OCH₃). 2.33 (s, 3H, CH₃) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=193.18 (C═O), 159.01 (d. ¹J_(CF)=269 Hz.Cq-F), 150.69 (Cq-O), 149.83 (Cq-O), 137.21 (CHar), 135.06 (CHar),133.43 (Cq), 131.64 (Cq), 131.51 (CHar), 128.50 (Cq), 128.43 (q.¹J_(CF)=259 Hz. CF₃), 128.38 (Cq), 127.52 (CHar), 126.13 (CHar), 124.40(Cq), 124.18 (CHar), 123.32 (Cq), 122.62 (CHar), 63.55 (OCH₃), 61.57(OCH₃), 12.77 (CH₃) ppm.

EI MS (70 eV, m/z (%): 392.0 ([M+], 25)

EXAMPLE 17 Synthesis of Compounds of Formula (Ib) 17.1. SelectiveDemethylation

General Procedure:

A solution of the1.4-dimethoxy-3-methylnaphthalen-2-yl)(substituted-phenyl)methanone (1.0equiv.) in dry DCM was cooled to 0° C. and kept stirring for 30 min.Then, BBr3 (1.0 equiv., 1M in DCM) was added dropwise to the solutionand the reaction mixture was stirred at 0° C. for 2 h (TLC control). Thereaction mixture was quenched with MeOH. Saturated NaCl was added to themixture which was extracted three times with DCM and twice with EtOAc.The organic layers were combined, dried over MgSO₄ and evaporated.

17.1.1. (2-fluorophenyl)(1-hydroxy-4-methoxy-3-methylnaphthalen-2-yl)methanone LJ108

(1,4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluorophenyl)methanone LJ103(75 mg, 0.231 mmol) was treated according to general procedure 12.1. Theproduct was obtained as a yellow powder. Rf(Cyclohexane:DCM 3:2)=0.29.Yield=68 mg (94%).

¹³C NMR (75 MHz, CDCl₃): δ=197.52 (C═O), 159.33 (d, ¹J_(CF)=253 Hz,Cq-F), 158.69 (Cq), 146.71 (Cq), 133.28 (d, ³J_(CF)=8 Hz, CHar), 131.92(Cq), 130.43 (CHar), 130.20 (d, ²J_(CF)=14 Hz, Cq-F), 129.76 (d,⁴J_(CF)=3 Hz, CHar), 125.72 (CHar), 124.92 (CHar), 124.56 (d, ³J_(CF)=6Hz, CHar-F), 123.38 (Cq), 123.36 (Cq), 121.80 (CHar), 116.42 (d,²J_(CF)=21 Hz, CHar), 116.44 (Cq), 61.10 (OCH₃), 15.43 (CH₃) ppm.

EI MS (70 eV, m/z (%): 310.1 ([M+], 21)

17.1.2.2-fluoro-3-(trifluoromethyl)phenyl)(1-hydroxy-4-methoxy-3-methylnaphthalen-2-yl)methanoneLJ118

(1,4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanoneLJ116 (40 mg, 0.102 mmol) was used as a starting material and treatedaccording to general procedure 12.1. The resulting dark yellow oil waspurified through flash chromatography (Cyclohexane:EtOAc 10:1). Theproduct was obtained as a bright yellow oil. Rf(Cyclohexane:EtOAc10:1)=0.23. Yield=15 mg (38%).

¹³C NMR (75 MHz, CDCl₃): δ=195.51 (C═O), 159.51 (Cq-O), 156.48 (dd,¹J_(CF)=262 Hz, ³J_(CF)=6 Hz, Cq-F), 146.99 (Cq-O), 133.47 (CHar),132.22 (Cq), 131.56 (d, ²J_(CF)=14 Hz, Cq), 130.87 (CHar), 129.92(CHar), 125.96 (CHar), 125.02 (CHar), 124.89 (Cq), 124.65 (CHar), 122.66(Cq), 122.21 (q, ¹J_(CF)=273 Hz, CF₃) 121.90 (CHar), 119.33 (dq,²J_(CF)=33 Hz, Cq-CF₃) 116.08 (Cq), 61.09 (OCH₃), 15.51 (CH₃) ppm.

¹⁹F NMR (282 MHz, CDCl₃): δ=−61.49 (d, ⁴J_(FF)=13 Hz, CF₃), −115.91(⁴J_(FF)=13 Hz, ⁴J_(HF)=6 Hz, F) ppm.

EI MS (70 eV, m/z (%): 378.3 ([M+], 48)

17.1.3.(2-fluoro-4-(trifluoromethyl)phenyl)(1-hydroxy-4-methoxy-3-methylnaphthalen-2-yl)methanoneLJ130

(1,4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluoro-4-(trifluoromethyl)phenyl)methanone LJ123 (23 mg, 0.060 mmol) was used as a startingmaterial and treated according to general procedure 12.1. The resultingyellow oil was purified through flash chromatography (DCM:Cyclohexane1:1). The product was obtained as a yellow solid. Rf(DCM:Cyclohexane1:1)=0.55. Yield=15 mg (68%).

¹H NMR (300 MHz, CDCl₃): δ=12.87 (OH), 8.48-8.50 (m, 1H), 8.00-8.03 (m,1H), 7.69-7.74 (m, 1H), 7.52-7.63 (cm, 3H), 7.43-7.46 (m, 1H), 3.82 (s,3H, OCH₃), 1.98 (s, 3H, CH₃) ppm.

¹⁹F NMR (282 MHz, CDCl₃): δ=−63.01 (s, CF₃), −111.93 (dd, ³J_(HF)=10 Hz,⁴J_(HF)=7 Hz, F) ppm.

EI MS (70 eV, m/z (%): 378.0 ([M+], 100), 363.0 (52), 345.0 (35).

17.2. Double Demethylation

General Procedure:

The general procedure followed the process for preparation of thefollowing compound.

17.2.1.(1,4-dihydroxy-3-methylnaphthalen-2-yl)(2-fluoro-4-(trifluoromethyl)phenyl)methanone LJ139

(1,4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluoro-4-(trifluoromethyl)phenyl)methanoneLJ123 (250 mg, 0.64 mmol) dissolved in 40 mL DCM was cooled to 0° C. andkept stirring for 30 min. Pure BBr₃ (122 μL, 1.27 mmol, 2.0 equiv.) wasadded dropwise to the solution and the reaction mixture was stirred at0° C. for 1 h. The reaction mixture was quenched with 60 mL MeOH.Saturated NaCl was added to the mixture and it was extracted with DCM(2×50 mL). The organic layer wad dried over MgSO₄ and evaporated to give300 mg of a red-orange solid. The red-orange residue was recrystallisedin 10 mL of a 10:1 Cyclohexane:EtOAc mixture. The product was obtainedas bright orange crystals. Yield=220 mg (94%).

m.p. 104° C. (dec.)

¹H NMR (300 MHz, CDCl₃): δ=12.55 (s, 1H, OH), 8.46-8.49 (m, 1H),8.06-8.09 (m, 1H), 7.69-7.74 (cm, 1H), 7.51-7.62 (cm, 3H), 7.42-7.46 (m,1H), 4.68 (s, 1H, OH), 1.94 (s, 3H, CH₃) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=194.45 (C═O), 161.87 (Cq-OH), 159.31 (Cq-OH),147.61 (d, ¹J_(CF)=300 Hz, Cq-F), 144.79 (Cq), 143.80 (Cq), 134.15 (dq,²J_(CF)=33 Hz, ³J_(CF)=9 Hz, Cq-CF₃), 132.68 (CHar), 131.76 (Cq), 127.93(Cq), 127.19 (CHar), 125.45 (CHar), 124.98 (d, ²J_(CF)=23 Hz, Cq),122.85 (CHar), 122.71 (CHar), 122.10 (CHar), 116.28 (Cq), 114.89 (dd,²J_(CF)=25 Hz, ³J_(CF)=4 Hz, CHar), 13.76 (CH₃) ppm.

¹⁹F NMR (CDCl₃, 282 MHz): δ=−63.44 (s, CF₃), −111.44 (dd, ³J_(HF)=10 Hz,⁴J_(HF)=7 Hz, F) ppm.

EI MS (70 eV, m/z (%): 364.1 ([M+], 100)

EA calcd for C₁₉H₁₂O₃F₄ (%): C, 62.64; H, 3.32; O, 13.18. Found: C,62.20; H, 3.08.

17.3. Access to Benzoxanthones by Intramolecular Cyclization

General Procedure: The benzophenone derivative (1.0 equiv.) and K₂CO₃(2.0 equiv.) were placed in a round-bottom flask. The flask was sealedunder Argon and 10 mL of dry Acetone were added. The reaction mixturewas stirred at 50° C. for 2 h. The suspension was then filtered througha pad of celite and washed with 25 mL Et₂O. The filtrate wasconcentrated under vacuo. The resulting product was purified throughflash chromatography.

17.3.1. 5-methoxy-6-methyl-7H-benzo[c]xanthen-7-one LJ115

(2-fluorophenyl)(1-hydroxy-4-methoxy-3-methylnaphthalen-2-yl)methanoneLJ103 (150 mg. 0.483 mmol) was used as a starting material and treatedaccording to general procedure 12.3. The product was obtained as anorange powder. Rf(Cyclohexane:EtOAc 10:1)=0.36. Yield=96 mg (69%).

¹H NMR (300 MHz, CDCl₃): δ=8.61-8.64 (m, 1H), 8.31-8.34 (m, 1H),8.13-8.16 (m, 1H), 7.69-7.75 (m, 2H), 7.58-7.65 (m, 2H), 7.37-7.42 (cm,1H), 3.91 (s, 3H, OCH₃), 2.96 (s, 3H, CH₃) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=178.68 (C═O), 154.81 (Cq-O), 151.84 (Cq-O),149.81 (Cq-O), 133.93 (CHar), 130.99 (Cq), 129.87 (CHar), 126.57 (CHar),126.29 (CHar), 125.86 (Cq), 124.22 (CHar), 123.79 (Cq), 123.28 (CHar),123.21 (Cq), 122.17 (CHar), 117.46 (CHar), 117.35 (Cq), 61.45 (OCH₃),14.51 (CH₃) ppm.

EI MS (70 eV, m/z (%): 290.1 ([M+], 53)

EA calcd for C₁₉H₁₄O₃ (%): C, 78.61; H, 4.86; O, 16.53. Found: C, 78.81;H, 4.92.

Mp=175-177° C.

17.3.2. 5-methoxy-6-methyl-11-(trifluoromethyl)-7H-benzo[c]xanthen-7-oneLJ119

(2-fluoro-3-(trifluoromethyl)phenyl)(1-hydroxy-4-methoxy-3-methylnaphthalen-2-yl)methanoneLJ118 (15 mg. 0.040 mmol) was used as a starting material and treatedaccording to general procedure 12.3. The product was obtained as a lightyellow cotton-like solid.

Yield=12 mg (86%).

¹H NMR (300 MHz, CDCl₃): δ=8.66-8.68 (m, 1H), 8.54-8.57 (m, 1H),8.17-8.20 (m, 1H), 8.02-8.05 (m, 1H), 7.76-7.82 (cm, 1H), 7.67-7.73 (cm,1H), 7.47-7.53 (cm, 1), 3.92 (s. 3H. OCH₃), 2.97 (s. 3H. CH₃) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=177.39 (C═O), 151.79 (Cq-O), 151.52 (Cq-O),150.50 (Cq-O), 131.27 (q. ³J_(CF)=4 Hz. CHar), 130.99 (CHar), 130.30(CHar), 126.92 (CHar), 125.56 (Cq), 124.05 (Cq), 123.70 (Cq), 123.49(CHar), 123.34 (CHar), 123.13 (q. ¹J_(CF)=273 Hz. CF₃), 122.15 (CHar),119.70 (Cq), 119.08 (q. ²J_(CF)=32 Hz. Cq-CF₃), 117.32 (Cq), 61.54(OCH₃), 14.46 (CH₃) ppm.

¹⁹F NMR (282 MHz, CDCl₃): δ=−61.31 (s, CF₃)

EI MS (70 eV, m/z (%): 358.0 ([M+]. 60), 343.0 (100).

EA calcd for C₂₀H₁₃O₃F₃ (%): C, 67.04; H, 3.66; O, 13.40. Found: C,66.95; H, 3.80.

Mp=198-200° C.

17.3.3. 5-methoxy-6-methyl-10-(trifluoromethyl)-7H-benzo[c]xanthen-7-oneLJ128

(2-fluoro-4-(trifluoromethyl)phenyl)(1-hydroxy-4-methoxy-3-methylnaphthalen-2-yl)methanoneLJ130 (15 mg. 0.040 mmol) was used as a starting material and treatedaccording to general procedure 12.3. The product was obtained as a whitecotton-like solid. Rf(DCM:Cyclohexane 1:1)=0.37. Yield=11 mg (79%).

¹H NMR (300 MHz, CDCl₃): δ=8.66-8.69 (m, 1H), 8.46-8.49 (m, 1H),8.18-8.21 (m, 1H), 7.96 (s, 1H), 7.77-7.82 (cm, 1H), 7.64-7.72 (m, 2H),3.93 (s, 3H, OCH₃), 2.96 (s, 3H, CH₃) ppm.

¹³C NMR (75 MHz, CDCl₃): δ=177.66 (C═O), 154.23 (Cq-O), 152.02 (Cq-O),150.33 (Cq-O), 135.40 (q. ²J_(CF)=33 Hz. Cq-CF₃), 131.25 (Cq), 130.27(CHar), 127.94 (CHar), 126.64 (CHar), 125.71 (Cq), 125.20 (Cq), 123.53(Cq), 123.28 (q. ¹J_(CF)=273 Hz. CF₃), 123.18 (CHar), 122.30 (CHar),120.53 (q. ³J_(CF)=4 Hz. CHar), 117.53 (Cq), 115.47 (q. ³J_(CF)=4 Hz.CHar), 61.48 (OCH₃), 14.46 (CH₃) ppm.

¹⁹F NMR (CDCl₃, 282 MHz): δ=−62.95 (s, CF₃)

EI MS (70 eV, m/z (%): 358.0 ([M+], 53)

EA calcd for C₂₀H₁₃O₃F₃ (%): C, 67.04; H. 3.66; O, 13.40; F, 15.91.Found: C, 66.64; H, 3.81.

Mp=167-169° C.

17.3.4. 5-hydroxy-6-methyl-10-(trifluoromethyl)-7H-benzo[c]xanthen-7-oneLJ144

(1,4-dihydroxy-3-methylnaphthalen-2-yl)(2-fluoro-4-(trifluoromethyl)phenyl)methanone LJ139 (100 mg. 0.275 mmol) was used as a starting material andtreated according to general procedure 12.3. The resulting red-orangesolid (90 mg) was recrystallised in 5 mL of a 10:1:0.1Cyclohexane:EtOAc:Acetone mixture. The product was obtained as a brightyellow powder. Yield=60 mg (63%).

¹H NMR (300 MHz, CDCl₃): δ=8.64-8.67 (m, 1H). 8.46-8.48 (m, 1H).8.28-8.31 (m, 1H). 7.95 (s, 1H). 7.63-7.81 (m, 3H). 5.33 (s, 1H, OH).2.96 (s, 3H, CH₃) ppm.

¹³C NMR (75 MHz, DMSO-d⁶): δ=176.89 (C═O), 153.76 (Cq-O), 148.98 (Cq-O),146.30 (Cq-O), 133.48 (Cq-CF₃), 126.87 (q, ¹J_(CF)=273 Hz, CF₃), 129.68(CHar), 127.58, (CHar), 126.61 (CHar), 125.20 (Cq), 122.74 (CHar),122.39 (Cq), 122.32 (CHar), 121.58 (Cq), 120.12 (CHar), 116.94 (Cq),116.09 (Cq), 115.93 (CHar), 13.76 (CH₃) ppm.

¹⁹F NMR (CDCl₃, 282 MHz): δ=−63.03 (s, CF₃) ppm.

EI MS (70 eV, m/z (%): 344.0 ([M+], 100)

EA calcd for C₁₉H₁₁O₃F₃ (%): C, 66.28%; H, 3.22%; O, 13.94%; F, 16.55%.Found: C, 66.23%; H, 3.58%.

Mp=229-231° C.

EXAMPLE 18 Inhibition of the Hematin Polymerisation 18.1. Material andMethod

The antischistosomial effect is measured by the evaluation of theability of the compounds to inhibit hematin polymerization according tothe biochemical assay previously developed by Ncokazi. K. K. Egan. T. J.Anal. Biochem. 2005, 338, 306-319 adapted to the compounds of thepresent invention. The assays were monitored by UV-Vis absorptionspectrophotometry and IC₅₀ values for inhibition of β-hematin formationwere determined from the absorbance at 405 nm versus the drug(equiv.)/hematin (equiv.) ratio.

18.2. Results

They are given in the table below:

Maximum IC₅₀ inhibition drug (equiv.)/ Compound Structure (%) hematin(equiv.) ratio LJ186

80 4.2 LJ144K

75 2.5

The two compounds LJ83K (=PTM58) and LJ186 are very potent inhibitors ofthe β-hematin polymerization. Both 3-benzylnaphtoquinone derivativesform 1:2 or 2:1 complexes with hematin displaying apparent associationconstants at pH 7.5 of about 10¹¹-10¹³ M⁻¹. Also the benzoxanthonederivative LJ144K form 1:1 charge-transfer complexes with hematindisplaying apparent association constants at pH 7.5 of about 10⁵-10⁶M⁻¹. These thermodynamic values are comparable to those reported in theliterature for antiparasitic xanthones targeting hematin polymerization(Monti. D., Vodopivec. B., Basilico. N., Olliaro. P., Taramelli. D.Biochemistry 1999, 38, 8858-8863).

EXAMPLE 19 Effect Against P. falciparum Strains 19.1. Material andMethods

The library of representative compounds was tested for antimalarialeffects using the ³H-hypoxanthine incorporation-based assay (FIG. 1).Inhibition of the growth of P. falciparum by the compounds was evaluatedby determining the inhibitor concentration required for killing 50% ofthe parasite (IC₅₀ values). In a screening assay all compounds weretested against the CQ-resistant P. falciparum strain Dd2.

In Vitro Antiparasitic Bioassays.

P. falciparum in vitro culture was carried out using standard protocols(Trager, W.; Jensen, J. B. Science 1976, 193, 673-675) withmodifications (Friebolin, W.; Jannack, B.; Wenzel, N.; Furrer, J.;Oeser, T.; Sanchez, C. P.; Lanzer, M.; Yardley, V.; Becker, K.;Davioud-Charvet, E. J. Med. Chem. 2008, 51, 1260-1277). Drugsusceptibility of P. falciparum was studied using a modified method(O'Brien, J.; Wilson, I.; Orton, T.; Pognan, F. Eur. J. Biochem. 2000,267, 5421-5426) of the protocol described previously for the³H-hypoxanthine incorporation-based assay (Desjardins, R. E.; Canfield,C. J.; Haynes, J. D.; Chulay, J. D. Antimicrob. Agents Chemother. 1979,16, 710-718). All assays included CQ diphosphate (Sigma, UK) as standardand control wells with untreated infected and uninfected erythrocytes.IC₅₀ values were derived by sigmoidal regression analysis (Microsoftx/fit™)

Determination of IC₅₀ Values Against Dd2 P. falciparum Strain.

The IC₅₀ was tested by standard in vitro antiproliferation assays basedon the ³H-hypoxanthine incorporation. Infected erythrocytes in ringstage (0.5% parasitemia, 2.5% hematocrit) in 96-well plates were exposedto the compounds for 48 h and then to radioactive hypoxanthine for 24 h.The amount of radioactivity in precipitable material served as an indexof cell proliferation. Chloroquine was added as reference and displayedan IC₅₀ value of 110 nM.

19.2. Results

They are given in FIG. 1. The most effective compounds in killingPlasmodium falciparum are the 6- and 7-substituted naphthoquinones, inparticular the 6- and the 7-fluoro menadione analogues, DAL54 and EC060,of the lead compounds P_TM24 or P_TM29, and thepyridinyl-4-methyl-substituted menadione LJ186. These compounds werefound more active than chloroquine or as active as P_TM29 in assaysusing the multi-resistant P. falciparum strain Dd2. Using theKochi-Anderson reaction from structurally diverse phenyl acetic acids,4-pyridylacetic acid and polysubstituted menadiones, synthesizedaccording the present processes of preparation, the preparation ofvarious 3-benzyl menadiones derivatives, substituted at 6- and 7- of themenadione core, and pyridinyl-4-methyl-substituted menadione LJ186analogues was applied.

Also, new azanaphthoquinones were constructed from Diels-Alder reactionand various aza-analogues were prepared and tested as antimalarialagents in assays using the multi-resistant P. falciparum strain Dd2.While various 6-methyl-7-(substituted-benzyl)quinoline-5,8-dione withstructures disclosed in the international application WO 2009/118327were tested and used as references in the antimalarial assays new azaanalogues, exemplified by7-methyl-6-(substituted-benzyl)quinoline-5,8-dione derivatives, werealso produced following the two-step sequence—Diels-Alder reaction andthen Kochi-Anderson reaction—and tested in the antimalarial assays.

Finally, putative metabolites of the antiparasitic(substituted-benzyl)menadione and (substituted-benzyl)azamenadionederivatives, generated from a cascade of redox reactions (FIG. 2), weresynthesized. They are illustrated with the benzoyl-naphthoquinones andbenzxanthones. They were tested in assays using thechloroquine-sensitive P. falciparum strain 3D7. The potential metaboliteLJ144K was found to display significant antimalarial effects with IC₅₀values in submicromolar range. The methylated precursors did not showantimalarial effects in the same range.

EXAMPLE 20 Effect Against S. mansoni Worms 20.1. Material and Methods

The compounds were tested to determine whether they could affect thesurvival of axenically cultured adult S. mansoni worms. Adult S. mansoniworms were cultured in the presence of different concentrations of theinhibitors and mobility and parasite death were monitored. Two groupswere used for each compound: one is drug alone, and the other isdrug+human RBCs (10 μl/well) or +10 μM hemoglobin (Hb). The finalconcentrations of compounds were 50 μM.

In Vitro Drug Treatments:

Compounds were dissolved in dimethylsulfoxide (DMSO) and added atconcentrations indicated to freshly perfused worms in RPMI1640containing 25 mM Hepes, pH 7, 150 units/ml penicillin, 125 μg/mlstreptomycin, and 10% fetal calf serum (Cell Grow, Fisher). Media werereplaced every two days with fresh media with addition of the compoundsat the designated concentrations. Control worms were treated with equalamounts of DMSO alone. Worms were subsequently observed for motility andmortality and collected at the indicated times for analysis.

In Vivo Drug Treatments:

Compound LJ83K was dissolved in DMSO and administrated byintraperitoneal injection to S. mansoni infected-mice (NIH-Swiss,National Cancer Institute) at 33 mg/kg once a day for 2 consecutive daysfollowing the schedule in FIG. 5. Compound LJ83K at this dosage has beenshown to be well tolerated by mice. Control S. mansoni-infected micewere administrated a corresponding amount of the drug carrier on thesame timetable. Age-matched uninfected mice were used as referencegroup.

Enzyme Assays:

Enzyme preparation and assays were as described as described (Kuntz A N,Davioud-Charvet E, Sayed A A, Califf L L, Dessolin J, Arnér E S,Williams D L. Thioredoxin glutathione reductase from Schistosomamansoni: an essential parasite enzyme and a key drug target. PLoS Med.2007 June; 4(6):e206) with 15 nM TGR at 25° C. in 0.1 M potassiumphosphate, pH 7.4, 10 mM EDTA. Thioredoxin reductase activity of TGR wasdetermined using either 3 mM 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB,Ellman's reagent) or 10 μM recombinant 6-histidine tagged S. mansonithioredoxin-2 (DLW and al., unpublished). One enzyme unit was defined asthe NADPH-dependent production of 2 μmol of 2-nitro-5-thiobenzoic acidper minute using ε₄₁₂ nm=13.6 mM⁻¹ cm⁻¹ or the consumption of 1 μmol ofNADPH (ε₃₄₀ nm=6.22 mM⁻¹ cm⁻¹) during the first three minutes.Glutathione reductase activity was determined with 100 μM GSH disulfideand 100 μM NADPH by measuring the decrease in A₃₄₀ nm due to consumptionof NADPH (ε₃₄₀ nm=6.22 mM⁻¹ cm⁻¹) during the first three minutes. Eachassay was done in triplicate and each experiment was repeated threetimes.

20.2. Results

They are given in FIGS. 3 to 5.

Antiparasitic (substituted-benzyl)menadione and(substituted-benzyl)azamenadione derivatives, and their potentialmetabolites illustrated with the benzoyl-naphthoquinones andbenzxanthones, were tested in assays using Schistosoma mansoni worms inculture. To stimulate the drug metabolism in the parasites the testswere carried out in the absence or in the presence of hemoglobin or redblood cells (RBC). In the presence or in the absence of RBCs, the twomost active compounds, LJ83K (P_TM58) and LJ81K (P_TM60), exhibitedkilling effects on the parasites; the parasites developed a “hairyphenotype” with appearance of spicula on the tegument, 4 hours aftertreatment suggesting an important perturbation in the metabolism of theparasite (see FIG. 3). These schistosomicidal effects might be mediatedvia a prodrug effect through heme-catalyzed oxidation reactions,responsible for the release of metabolites including the3-benzoylmenadione derivatives acting as subversive substrates of thedisulfide reductases, i.e. both glutathione reductases of the infectedred blood cells, and the thioredoxin-glutathione reductase fromschistosomes. In the in vivo experiments, all injections were ip: thefirst injection was carried out six weeks post-infection, the second wasperformed two days later. Perfusion was 7 days after the secondinjection date. LJ83K was injected twice at 33 mg/kg (FIG. 5). LJ83Kadministration resulted in a significant, ca. 60% reduction (P=0.031) inworm burdens.

For azamenadiones designed in order to increase the solubility of thefinal naphthoquinones and for compounds designed to increase theresistance to oxidative metabolism in the worms the mobility of worms isdecreased (data not shown).

Among the polysubstituted P_TM29 analogues, DAL29-I135 and DAL48-I133could kill the parasites but survival rates were ca 50% after 48 hoursno significant difference in the survival rates was found between thepresence of and the absence of RBCs. It should be noted however thatDAL48-I33 treatment led to the worms to develop a hairy phenotype within48 hours. DAL50-I137 killed the parasites and RBCs could increase itspotency. DAL53-I141 could kill parasites (71% dead worms after 48 h) butno significant difference in the survival rates was found between thepresence of and the absence of RBCs (FIG. 4). Furthermore, the 6-chloroanalogue of P_TM29, EC050, exhibited the highest antischistosomal actionagainst ex vivo S. mansoni worms with 100% death after 24 h.

The invention claimed is:
 1. A method of treating a subject sufferingfrom a blood-feeding parasite of genus Eimeria, Babesia, or Schistosoma,comprising administering to said subject an effective amount of acompound of formula (Ia):

wherein: each of X₁, X₂, X₃ and X₄ represents a carbon atom, or eitherone of X₁, X₂, X₃ and X₄ represents a nitrogen atom, and each of thethree others of X₁, X₂, X₃ and X₄ represents a carbon atom, or each ofX₁ and X₄ represents a nitrogen atom and each of X₂ and X₃ represents acarbon atom; X₅ represents CO, CH₂ or CHOH; each of X₆, X₇, X₈, X₉ andX₁₀ represents a carbon atom, or one of X₆, X₇, X₈, X₉ and X₁₀represents a nitrogen atom and each of the four others of X₆, X₇, X₈, X₉and X₁₀ represents a carbon atom; X₁, X₂, X₃, and X₄, when they arecarbon atoms optionally being substituted with a hydrogen atom, ahalogen atom, a hydroxy group, a triflate group, a phosphate group, alinear or branched (C₁-C₄)alkyl group, a linear or branched(C₁-C₄)alkoxy group, a thio(C₁-C₄)alkoxy group, a pentafluorosulfanylgroup, —SCF₃, —SCH₂F, a trifluoromethyl group, or a trifluoromethoxygroup, and X₆, X₇, X₈, X₉, X₁₀, when they are carbon atoms optionallybeing substituted by a hydrogen atom, a halogen atom, a hydroxy group, alinear or branched (C₁-C₄)alkyl group, a linear or branched(C₁-C₄)alkoxy group, a thio(C₁-C₄)alkoxy group, a pentafluorosulfanylgroup, a trifluoromethyl group, a trifluoromethoxy group, adifluoromethoxy group, a difluoromethyl group, COOH, COO(C₁-C₄) alkylgroup, CONR₁(CH₂)_(m)CN with R₁ being a hydrogen atom or a linear orbranched (C₁-C₄)alkyl group and m=1, 2 or 3, CSNR₁(CH₂)_(m)CN with R₁being a hydrogen atom or a linear or branched (C₁-C₄)alkyl group m=1, 2or 3, CONR₁Het with R₁ being a hydrogen atom or a linear or branched(C₁-C₄) alkyl group and Het representing a pyridine-2-yl group, saidpyridine-2-yl group optionally substituted by an amino group in -6 or bya —CONH₂ group in -5, NO₂, CN, NR₂R₃ with R₂ and R₃ each independentlyrepresenting a hydrogen atom, an amino protecting group that is a Bocgroup or a (C₁-C₄) alkyl group, or R₂ and R₃ forming with the nitrogenatom which bears them a cyclic group selected from the group consistingof morpholine, piperidine, and piperazine groups, said cyclic groupsbeing optionally substituted, an aryl group or an aryl group substitutedby one or more substituents selected from the group consisting of a(C₁-C₄) alkyl group, a —NO₂ group, a —COOR₄ with R₄ being a hydrogenatom or a linear or branched (C₁-C₄) alkyl group, a —NR₅R₆ with R₅ andR₆ independently being a hydrogen atom or a linear or branched (C₁-C₄)alkyl group, or a heterocyclic group selected from the group consistingof a morpholinyl group, a piperidinyl group, and a piperazinyl group,each of said heterocyclic groups being optionally substituted by one ormore substituents selected from the group consisting of a linear orbranched (C₁-C₄)alkyl group, —COOCH₂CH₃, and a

group, and pharmaceutically acceptable derivatives thereof.
 2. A methodof preventing or reducing the incidence of a parasitic disease due toblood-feeding parasites of genus Eimeria, Babesia, or Schistosoma in asubject, comprising administering to the subject an effective amount ofa compound of formula (Ia):

wherein: each of X₁, X₂, X₃ and X₄ represents a carbon atom, or eitherone of X₁, X₂, X₃ and X₄ represents a nitrogen atom, and each of thethree others of X₁, X₂, X₃ and X₄ represents a carbon atom, or each ofX₁ and X₄ represents a nitrogen atom and each of X₂ and X₃ represents acarbon atom; X₅ represents CO, CH₂ or CHOH; each of X₆, X₇, X₈, X₉ andX₁₀ represents a carbon atom, or one of X₆, X₇, X₈, X₉ and X₁₀represents a nitrogen atom and each of the four others of X₆, X₇, X₈, X₉and X₁₀ represents a carbon atom; X₁, X₂, X₃, and X₄, when they arecarbon atoms optionally being substituted with a hydrogen atom, ahalogen atom, a hydroxy group, a triflate group, a phosphate group, alinear or branched (C₁-C₄)alkyl group, a linear or branched(C₁-C₄)alkoxy group, a thio(C₁-C₄)alkoxy group, a pentafluorosulfanylgroup, —SCF₃, —SCH₂F, a trifluoromethyl group, or a trifluoromethoxygroup, and X₆, X₇, X₈, X₉, X₁₀, when they are carbon atoms optionallybeing substituted by a hydrogen atom, a halogen atom, a hydroxy group, alinear or branched (C₁-C₄)alkyl group, a linear or branched(C₁-C₄)alkoxy group, a thio(C₁-C₄)alkoxy group, a pentafluorosulfanylgroup, a trifluoromethyl group, a trifluoromethoxy group, adifluoromethoxy group, a difluoromethyl group, COOH, COO (C₁-C₄) alkylgroup, CONR₁(CH₂)_(m)CN with R₁ being a hydrogen atom or a linear orbranched (C₁-C₄)alkyl group and m=1, 2 or 3, CSNR₁(CH₂)_(m)CN with R₁being a hydrogen atom or a linear or branched (C₁-C₄)alkyl group m=1, 2or 3, CONR₁Het with R₁ being a hydrogen atom or a linear or branched(C₁-C₄) alkyl group and Het representing a pyridine-2-yl group, saidpyridine-2-yl group optionally substituted by an amino group in -6 or bya —CONH₂ group in -5, NO₂, CN, NR₂R₃ with R₂ and R₃ each independentlyrepresenting a hydrogen atom, an amino protecting group that is a Bocgroup or a (C₁-C₄) alkyl group, or R₂ and R₃ forming with the nitrogenatom which bears them a cyclic group selected from the group consistingof morpholine, piperidine, and piperazine groups, said cyclic groupsbeing optionally substituted, an aryl group or an aryl group substitutedby one or more substituents selected from the group consisting of a(C₁-C₄) alkyl group, a —NO₂ group, a —COOR₄ with R₄ being a hydrogenatom or a linear or branched (C₁-C₄) alkyl group, a —NR₅R₆ with R₅ andR₆ independently being a hydrogen atom or a linear or branched (C₁-C₄)alkyl group, or a heterocyclic group selected from the group consistingof a morpholinyl group, a piperidinyl group, and a piperazinyl group,each of said heterocyclic groups being optionally substituted by one ormore substituents selected from the group consisting of a linear orbranched (C₁-C₄)alkyl group, —COOCH₂CH₃, and a

group, and pharmaceutically acceptable derivatives thereof.
 3. Themethod according to claim 1, wherein the compound is selected from thegroup consisting of:

wherein in each of Ia1, Ia2, Ia3, Ia4, Ia5 and Ia6: Z₁, Z₂, Z₃ and Z₄each independently represents a hydrogen atom, a halogen atom, a hydroxygroup, a triflate group, a phosphate group, a linear or branched(C₁-C₄)alkyl group, a linear or branched (C₁-C₄)alkoxy group, athio(C₁-C₄)alkoxy group, a pentafluorosulfanyl group, —SCF₃ —SCH₂F, atrifluoromethyl group, or a trifluoromethoxy group, and pharmaceuticallyacceptable derivatives thereof.
 4. The method according to claim 2,wherein the compound is of a formula selected from the group consistingof:

wherein in each of Ia1, Ia2, Ia3, Ia4, Ia5 and Ia6: Z₁, Z₂, Z₃ and Z₄each independently represents a hydrogen atom, a halogen atom, a hydroxygroup, a triflate group, a phosphate group, a linear or branched(C₁-C₄)alkyl group, a linear or branched (C₁-C₄)alkoxy group, athio(C₁-C₄)alkoxy group, a pentafluorosulfanyl group, —SCF₃ —SCH₂F, atrifluoromethyl group, or a trifluoromethoxy group; and pharmaceuticallyacceptable derivatives thereof.
 5. A method of treating a subjectsuffering from a parasitic disease due to Plasmodium, comprisingadministering to the subject an effective amount of a compound offormula (Ia):

wherein each of X₁, X₂, X₃ and X₄ represents a carbon atom, or X₁represents a carbon atom, one of X₂, X₃ and X₄ represents a nitrogenatom and each of the two others of X₂, X₃ and X₄ represents a carbonatom, or X₁ represents a nitrogen atom and each of X₂, X₃ and X₄represents a carbon atom, or each of X₁ and X₄ represents a nitrogenatom and each of X₂ and X₃ represents a carbon atom, X₅ represents CO,CH₂ or CHOH, each of X₆, X₇, X₈, X₉ and X₁₀ represents a carbon atom, orone of X₆, X₇, X₈, X₉ and X₁₀ represents a nitrogen atom and each of thefour others of X₆, X₇, X₈, X₉ and X₁₀ represents a carbon atom, X₁, X₂,X₃, X₄, when they are carbon atoms optionally being substituted with, ahydrogen atom, a halogen atom, a hydroxy group, a triflate group, aphosphate group, a linear or branched (C₁-C₄)alkyl group, a linear orbranched (C₁-C₄)alkoxy group, a thio(C₁-C₄)alkoxy group, apentafluorosulfanyl group, —SCF₃, —SCH₂F, a trifluoromethyl group, or atrifluoromethoxy group, and X₆, X₇, X₈, X₉, X₁₀, when they are carbonatoms optionally being substituted with a hydrogen atom, a halogen atom,a hydroxy group, a linear or branched (C₁-C₄)alkyl group, a linear orbranched (C₁-C₄)alkoxy group, a thio(C₁-C₄)alkoxy group, apentafluorosulfanyl group, a trifluoromethyl group, a trifluoromethoxygroup, a difluoromethoxy group, a difluoromethyl group, COOH, COO(C₁-C₄) alkyl group, CONR₁(CH₂)_(m)CN with R₁ being a hydrogen atom or alinear or branched (C₁-C₄)alkyl group and m=1, 2 or 3, CSNR₁(CH₂)_(m)CNwith R₁ being a hydrogen atom or a linear or branched (C₁-C₄)alkyl groupm=1, 2 or 3, CONR₁Het with R₁ being a hydrogen atom or a linear orbranched (C₁-C₄) alkyl group and Het representing a pyridine-2-yl group,said pyridine-2-yl group optionally substituted by an amino group in -6or by a —CONH₂ group in -5, NO₂, CN, NR₂R₃ with R₂ and R₃ eachindependently representing a hydrogen atom, an amino protecting groupthat is a Boc group or a (C₁-C₄) alkyl group, or R₂ and R₃ forming withthe nitrogen atom which bears them a cyclic group selected from thegroup consisting of morpholine, piperidine, and piperazine groups, saidcyclic groups being optionally substituted, an aryl group or an arylgroup substituted by one or more substituents selected from the groupconsisting of a (C₁-C₄) alkyl group, a —NO₂ group, a —COOR₄ with R₄being a hydrogen atom or a linear or branched (C₁-C₄) alkyl group, a—NR₅R₆ with R₅ and R₆ independently being a hydrogen atom or a linear orbranched (C₁-C₄) alkyl group, or a heterocyclic group selected from thegroup consisting of a morpholinyl group, a piperidinyl group, and apiperazinyl group, each of said heterocyclic groups being optionallysubstituted by one or more substituents selected from the groupconsisting of a linear or branched (C₁-C₄)alkyl group, —COOCH₂CH₃, and a

group, and pharmaceutically acceptable derivatives of the compoundthereof, with the proviso that: if each of X₁, X₂, X₃ and X₄ representsa carbon atom, or if X₁ represents a nitrogen atom, then at least one ofX₆, X₇, X₈, X₉ and X₁₀ represents a nitrogen atom.
 6. A method ofpreventing or reducing the incidence of a parasitic disease due toPlasmodium in a subject, comprising administering to the subject aneffective amount of the compound of formula (Ia):

wherein each of X₁, X₂, X₃ and X₄ represents a carbon atom, or X₁represents a carbon atom, one of X₂, X₃ and X₄ represents a nitrogenatom and each of the two others of X₂, X₃ and X₄ represents a carbonatom, or X₁ represents a nitrogen atom and each of X₂, X₃ and X₄represents a carbon atom, or each of X₁ and X₄ represents a nitrogenatom and each of X₂ and X₃ represents a carbon atom, X₅ represents CO,CH₂ or CHOH, each of X₆, X₇, X₈, X₉ and X₁₀ represents a carbon atom, orone of X₆, X₇, X₈, X₉ and X₁₀ represents a nitrogen atom and each of thefour others of X₆, X₇, X₈, X₉ and X₁₀ represents a carbon atom, and whenthey are carbon atoms optionally being substituted with a hydrogen atom,a halogen atom, a hydroxy group, a triflate group, a phosphate group, alinear or branched (C₁-C₄)alkyl group, a linear or branched(C₁-C₄)alkoxy group, a thio(C₁-C₄)alkoxy group, a pentafluorosulfanylgroup, —SCF₃, —SCH₂F, a trifluoromethyl group, or a trifluoromethoxygroup, and X₆, X₇, X₈, X₉, X₁₀, when they are carbon atoms optionallybeing substituted with a hydrogen atom, a halogen atom, a hydroxy group,a linear or branched (C₁-C₄)alkyl group, a linear or branched(C₁-C₄)alkoxy group, a thio(C₁-C₄)alkoxy group, a pentafluorosulfanylgroup, a trifluoromethyl group, a trifluoromethoxy group, adifluoromethoxy group, a difluoromethyl group, COOH, COO (C₁-C₄) alkylgroup, CONR₁(CH₂)_(m)CN with R₁ being a hydrogen atom or a linear orbranched (C₁-C₄)alkyl group and m=1, 2 or 3, CSNR₁(CH₂)_(m)CN with R₁being a hydrogen atom or a linear or branched (C₁-C₄)alkyl group m=1, 2or 3, CONR₁Het with R₁ being a hydrogen atom or a linear or branched(C₁-C₄) alkyl group and Het representing a pyridine-2-yl group, saidpyridine-2-yl group optionally substituted by an amino group in -6 or bya —CONH₂ group in -5, NO₂, CN, NR₂R₃ with R₂ and R₃ each independentlyrepresenting a hydrogen atom, an amino protecting group that is a Bocgroup or a (C₁-C₄) alkyl group, or R₂ and R₃ forming with the nitrogenatom which bears them a cyclic group selected from the group consistingof morpholine, piperidine, and piperazine groups, said cyclic groupsbeing optionally substituted, an aryl group or an aryl group substitutedby one or more substituents selected from the group consisting of a(C₁-C₄) alkyl group, a —NO₂ group, a —COOR₄ with R₄ being a hydrogenatom or a linear or branched (C₁-C₄) alkyl group, a —NR₅R₆ with R₅ andR₆ independently being a hydrogen atom or a linear or branched (C₁-C₄)alkyl group, or a heterocyclic group selected from the group consistingof a morpholinyl group, a piperidinyl group, and a piperazinyl group,each of said heterocyclic groups being optionally substituted by one ormore substituents selected from the group consisting of a linear orbranched (C₁-C₄)alkyl group, —COOCH₂CH₃, and a

group, and pharmaceutically acceptable derivatives of the compoundthereof, with the proviso that: if each of X₁, X₂, X₃ and X₄ representsa carbon atom, or if X₁ represents a nitrogen atom, then at least one ofX₆, X₇, X₈, X₉ and X₁₀ represents a nitrogen atom.
 7. The methodaccording to claim 5, wherein the compound is selected from the groupconsisting of:

wherein in each of Ia1, Ia2, Ia3, Ia4, Ia5 and Ia6: Z₁, Z₂, Z₃ and Z₄each independently represent, a hydrogen atom, a halogen atom, a hydroxygroup, a triflate group, a phosphate group, a linear or branched(C₁-C₄)alkyl group, a linear or branched (C₁-C₄)alkoxy group, athio(C₁-C₄)alkoxy group, a pentafluorosulfanyl group, —SCF₃ —SCH₂F, atrifluoromethyl group, or a trifluoromethoxy group, and pharmaceuticallyacceptable derivatives of the compound thereof, with the proviso that inthe compound of formula (Ia1) and in the compound of formula (Ia6) atleast one of X₆, X₇, X₈, X₉ and X₁₀ represents a nitrogen atom.
 8. Themethod according to claim 6, wherein the compound is selected from thegroup consisting of:

wherein Z₁, Z₂, Z₃ and Z₄ each independently represent, a hydrogen atom,a halogen atom, a hydroxy group, a triflate group, a phosphate group, alinear or branched (C₁-C₄)alkyl group, a linear or branched(C₁-C₄)alkoxy group, a thio(C₁-C₄)alkoxy group, a pentafluorosulfanylgroup, —SCF₃ —SCH₂F, a trifluoromethyl group, or a trifluoromethoxygroup, and pharmaceutically acceptable derivatives of the compoundthereof, with the proviso that in the compound of formula (Ia1) and inthe compound of formula (Ia6) one of X₆, X₇, X₈, X₉ and X₁₀ represents anitrogen atom.
 9. A method of treating a subject suffering from aparasitic disease due to Plasmodium, comprising administering to thesubject an effective amount of at least one of the following compounds:


10. A method of preventing or reducing the incidence of a parasiticdisease due to Plasmodium in a subject, comprising administering to thesubject an effective amount of at least one of the following compounds:


11. The method of claim 1, wherein the compound of formula (Ia) isselected from the group consisting of:


12. The method of claim 2, wherein the compound of formula (Ia) isselected from the group consisting of: